@article{
 title = {Development of Selective ADAMTS-5 Peptide Substrates to Monitor Proteinase Activity},
 type = {article},
 year = {2023},
 pages = {3522-3539},
 volume = {66},
 websites = {https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.2c02090},
 month = {3},
 publisher = {American Chemical Society},
 day = {9},
 id = {e8336b1d-a91f-37ec-a3a5-404a3da5fff5},
 created = {2023-05-14T11:55:18.762Z},
 accessed = {2023-05-14},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2023-05-16T12:56:53.914Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {The dysregulation of proteinase activity is a hallmark of osteoarthritis (OA), a disease characterized by progressive degradation of articular cartilage by catabolic proteinases such as a disintegrin and metalloproteinase with thrombospondin type I motifs-5 (ADAMTS-5). The ability to detect such activity sensitively would aid disease diagnosis and the evaluation of targeted therapies. Förster resonance energy transfer (FRET) peptide substrates can detect and monitor disease-related proteinase activity. To date, FRET probes for detecting ADAMTS-5 activity are nonselective and relatively insensitive. We describe the development of rapidly cleaved and highly selective ADAMTS-5 FRET peptide substrates through in silico docking and combinatorial chemistry. The lead substrates 3 and 26 showed higher overall cleavage rates (∼3-4-fold) and catalytic efficiencies (∼1.5-2-fold) compared to the best current ADAMTS-5 substrate ortho-aminobenzoyl(Abz)-TESE↓SRGAIY-N-3-[2,4-dinitrophenyl]-l-2,3-diaminopropionyl(Dpa)-KK-NH2. They exhibited high selectivity for ADAMTS-5 over ADAMTS-4 (∼13-16-fold), MMP-2 (∼8-10-fold), and MMP-9 (∼548-2561-fold) and detected low nanomolar concentrations of ADAMTS-5.},
 bibtype = {article},
 author = {Fowkes, Milan M. and Troeberg, Linda and Brennan, Paul E. and Vincent, Tonia L. and Meldal, Morten and Lim, Ngee H.},
 doi = {10.1021/ACS.JMEDCHEM.2C02090/SUPPL_FILE/JM2C02090_SI_002.PDF},
 journal = {Journal of Medicinal Chemistry},
 number = {5}
}

The dysregulation of proteinase activity is a hallmark of osteoarthritis (OA), a disease characterized by progressive degradation of articular cartilage by catabolic proteinases such as a disintegrin and metalloproteinase with thrombospondin type I motifs-5 (ADAMTS-5). The ability to detect such activity sensitively would aid disease diagnosis and the evaluation of targeted therapies. Förster resonance energy transfer (FRET) peptide substrates can detect and monitor disease-related proteinase activity. To date, FRET probes for detecting ADAMTS-5 activity are nonselective and relatively insensitive. We describe the development of rapidly cleaved and highly selective ADAMTS-5 FRET peptide substrates through in silico docking and combinatorial chemistry. The lead substrates 3 and 26 showed higher overall cleavage rates (∼3-4-fold) and catalytic efficiencies (∼1.5-2-fold) compared to the best current ADAMTS-5 substrate ortho-aminobenzoyl(Abz)-TESE↓SRGAIY-N-3-[2,4-dinitrophenyl]-l-2,3-diaminopropionyl(Dpa)-KK-NH2. They exhibited high selectivity for ADAMTS-5 over ADAMTS-4 (∼13-16-fold), MMP-2 (∼8-10-fold), and MMP-9 (∼548-2561-fold) and detected low nanomolar concentrations of ADAMTS-5.

@article{
 title = {The X-linked histone demethylases KDM5C and KDM6A as regulators of T cell-driven autoimmunity in the central nervous system.},
 type = {article},
 year = {2023},
 pages = {110748},
 volume = {202},
 month = {10},
 id = {a7e3e7ac-bede-3e7a-8dcd-f6b068ce6d04},
 created = {2023-10-23T10:42:00.757Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2023-10-23T10:42:00.757Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {fazazi2023thesystem},
 source_type = {article},
 medium = {Print-Electronic},
 private_publication = {false},
 abstract = {T cell-driven autoimmune responses are subject to striking sex-dependent effects. While the contributions of sex hormones are well-understood, those of sex chromosomes are meeting with increased appreciation. Here, we outline what is known about the contribution of sex chromosome-linked factors to experimental autoimmune encephalomyelitis (EAE), a mouse model that recapitulates many of the T cell-driven mechanisms of multiple sclerosis (MS) pathology. Particular attention is paid to the KDM family of histone demethylases, several of which - KDM5C, KDM5D and KDM6A - are sex chromosome encoded. Finally, we provide evidence that functional inhibition of KDM5 molecules can suppress interferon (IFN)γ production from murine male effector T cells, and that an increased ratio of inflammatory Kdm6a to immunomodulatory Kdm5c transcript is observed in T helper 17 (Th17) cells from women with the autoimmune disorder ankylosing spondylitis (AS). Histone lysine demethlyases thus represent intriguing targets for the treatment of T cell-driven autoimmune disorders.},
 bibtype = {article},
 author = {Fazazi, M R and Ruda, G F and Brennan, P E and Rangachari, M},
 doi = {10.1016/j.brainresbull.2023.110748},
 journal = {Brain research bulletin}
}

T cell-driven autoimmune responses are subject to striking sex-dependent effects. While the contributions of sex hormones are well-understood, those of sex chromosomes are meeting with increased appreciation. Here, we outline what is known about the contribution of sex chromosome-linked factors to experimental autoimmune encephalomyelitis (EAE), a mouse model that recapitulates many of the T cell-driven mechanisms of multiple sclerosis (MS) pathology. Particular attention is paid to the KDM family of histone demethylases, several of which - KDM5C, KDM5D and KDM6A - are sex chromosome encoded. Finally, we provide evidence that functional inhibition of KDM5 molecules can suppress interferon (IFN)γ production from murine male effector T cells, and that an increased ratio of inflammatory Kdm6a to immunomodulatory Kdm5c transcript is observed in T helper 17 (Th17) cells from women with the autoimmune disorder ankylosing spondylitis (AS). Histone lysine demethlyases thus represent intriguing targets for the treatment of T cell-driven autoimmune disorders.

@article{
 title = {Open drug discovery in Alzheimer's disease.},
 type = {article},
 year = {2023},
 pages = {e12394},
 volume = {9},
 month = {4},
 id = {2c994b59-0342-3938-8db5-b7c101a132b7},
 created = {2023-10-23T10:42:00.774Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2023-10-23T10:42:00.774Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {axtman2023opendisease},
 source_type = {article},
 medium = {Electronic-eCollection},
 private_publication = {false},
 abstract = {Alzheimer's disease (AD) drug discovery has focused on a set of highly studied therapeutic hypotheses, with limited success. The heterogeneous nature of AD processes suggests that a more diverse, systems-integrated strategy may identify new therapeutic hypotheses. Although many target hypotheses have arisen from systems-level modeling of human disease, in practice and for many reasons, it has proven challenging to translate them into drug discovery pipelines. First, many hypotheses implicate protein targets and/or biological mechanisms that are under-studied, meaning there is a paucity of evidence to inform experimental strategies as well as high-quality reagents to perform them. Second, systems-level targets are predicted to act in concert, requiring adaptations in how we characterize new drug targets. Here we posit that the development and open distribution of high-quality experimental reagents and informatic outputs-termed target enabling packages (TEPs)-will catalyze rapid evaluation of emerging systems-integrated targets in AD by enabling parallel, independent, and unencumbered research.},
 bibtype = {article},
 author = {Axtman, A D and Brennan, P E and Frappier-Brinton, T and Betarbet, R and Carter, G W and Fu, H and Gileadi, O and Greenwood, A K and Leal, K and Longo, F M and Mangravite, L M and Edwards, A M and Levey, A I and Center, Emory‐Sage‐SGC TREAT‐AD},
 doi = {10.1002/trc2.12394},
 journal = {Alzheimer's \& dementia (New York, N. Y.)},
 number = {2}
}

Alzheimer's disease (AD) drug discovery has focused on a set of highly studied therapeutic hypotheses, with limited success. The heterogeneous nature of AD processes suggests that a more diverse, systems-integrated strategy may identify new therapeutic hypotheses. Although many target hypotheses have arisen from systems-level modeling of human disease, in practice and for many reasons, it has proven challenging to translate them into drug discovery pipelines. First, many hypotheses implicate protein targets and/or biological mechanisms that are under-studied, meaning there is a paucity of evidence to inform experimental strategies as well as high-quality reagents to perform them. Second, systems-level targets are predicted to act in concert, requiring adaptations in how we characterize new drug targets. Here we posit that the development and open distribution of high-quality experimental reagents and informatic outputs-termed target enabling packages (TEPs)-will catalyze rapid evaluation of emerging systems-integrated targets in AD by enabling parallel, independent, and unencumbered research.

@article{
 title = {Discovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain Inhibitors.},
 type = {article},
 year = {2023},
 pages = {324},
 volume = {12},
 month = {2},
 id = {a4297b41-6c4c-393a-978f-a4370afc1f66},
 created = {2023-10-23T10:42:00.816Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2023-10-23T10:42:00.816Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {schuller2023discoveryinhibitors},
 source_type = {article},
 medium = {Electronic},
 private_publication = {false},
 abstract = {The worldwide public health and socioeconomic consequences caused by the COVID-19 pandemic highlight the importance of increasing preparedness for viral disease outbreaks by providing rapid disease prevention and treatment strategies. The NSP3 macrodomain of coronaviruses including SARS-CoV-2 is among the viral protein repertoire that was identified as a potential target for the development of antiviral agents, due to its critical role in viral replication and consequent pathogenicity in the host. By combining virtual and biophysical screening efforts, we discovered several experimental small molecules and FDA-approved drugs as inhibitors of the NSP3 macrodomain. Analogue characterisation of the hit matter and crystallographic studies confirming binding modes, including that of the antibiotic compound aztreonam, to the active site of the macrodomain provide valuable structure-activity relationship information that support current approaches and open up new avenues for NSP3 macrodomain inhibitor development.},
 bibtype = {article},
 author = {Schuller, M and Zarganes-Tzitzikas, T and Bennett, J and De Cesco, S and Fearon, D and von Delft, F and Fedorov, O and Brennan, P E and Ahel, I},
 doi = {10.3390/pathogens12020324},
 journal = {Pathogens (Basel, Switzerland)},
 number = {2}
}

The worldwide public health and socioeconomic consequences caused by the COVID-19 pandemic highlight the importance of increasing preparedness for viral disease outbreaks by providing rapid disease prevention and treatment strategies. The NSP3 macrodomain of coronaviruses including SARS-CoV-2 is among the viral protein repertoire that was identified as a potential target for the development of antiviral agents, due to its critical role in viral replication and consequent pathogenicity in the host. By combining virtual and biophysical screening efforts, we discovered several experimental small molecules and FDA-approved drugs as inhibitors of the NSP3 macrodomain. Analogue characterisation of the hit matter and crystallographic studies confirming binding modes, including that of the antibiotic compound aztreonam, to the active site of the macrodomain provide valuable structure-activity relationship information that support current approaches and open up new avenues for NSP3 macrodomain inhibitor development.

@article{
 title = {Structural premise of selective deubiquitinase USP30 inhibition by small-molecule benzosulfonamides},
 type = {article},
 year = {2023},
 volume = {22},
 month = {6},
 publisher = {Elsevier},
 id = {8adc71ba-e994-3c4a-8d6b-032d9fb8ace6},
 created = {2023-10-23T10:42:00.827Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2023-10-23T10:42:00.827Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {obrien2023structuralbenzosulfonamides},
 source_type = {article},
 private_publication = {false},
 abstract = {Dampening functional levels of the mitochondrial deubiquitylating enzyme Ubiquitin-specific protease 30 (USP30) has been suggested as an effective therapeutic strategy against neurodegenerative disorders such as Parkinson’s Disease. USP30 inhibition may counteract the deleterious effects of impaired turnover of damaged mitochondria, which is inherent to both familial and sporadic forms of the disease. Small-molecule inhibitors targeting USP30 are currently in development, but little is known about their precise nature of binding to the protein. We have integrated biochemical and structural approaches to gain novel mechanistic insights into USP30 inhibition by a small-molecule benzosulfonamide-containing compound, USP30<sub>inh</sub>. Activity-based protein profiling mass spectrometry confirmed target engagement, high selectivity, and potency of USP30<sub>inh</sub> for USP30 against 49 other deubiquitylating enzymes in a neuroblastoma cell line. <i>In vitro</i> characterization of USP30<sub>inh</sub> enzyme kinetics inferred slow and tight binding behavior, which is comparable with features of covalent modification of USP30. Finally, we blended hydrogen–deuterium exchange mass spectrometry and computational docking to elucidate the molecular architecture and geometry of USP30 complex formation with USP30<sub>inh</sub>, identifying structural rearrangements at the cleft of the USP30 thumb and palm subdomains. These studies suggest that USP30<sub>inh</sub> binds to this thumb–palm cleft, which guides the ubiquitin C terminus into the active site, thereby preventing ubiquitin binding and isopeptide bond cleavage, and confirming its importance in the inhibitory process. Our data will pave the way for the design and development of next-generation inhibitors targeting USP30 and associated deubiquitinylases.},
 bibtype = {article},
 author = {O'Brien, D P and Jones, H B L and Guenther, F and Murphy, E J and England, K S and Vendrell, I and Anderson, M and Brennan, P E and Davis, J B and Pinto-Fernández, A and Turnbull, A P and Kessler, B M},
 doi = {10.1016/j.mcpro.2023.100609},
 journal = {Molecular \& Cellular Proteomics},
 number = {8}
}

Dampening functional levels of the mitochondrial deubiquitylating enzyme Ubiquitin-specific protease 30 (USP30) has been suggested as an effective therapeutic strategy against neurodegenerative disorders such as Parkinson’s Disease. USP30 inhibition may counteract the deleterious effects of impaired turnover of damaged mitochondria, which is inherent to both familial and sporadic forms of the disease. Small-molecule inhibitors targeting USP30 are currently in development, but little is known about their precise nature of binding to the protein. We have integrated biochemical and structural approaches to gain novel mechanistic insights into USP30 inhibition by a small-molecule benzosulfonamide-containing compound, USP30_inh. Activity-based protein profiling mass spectrometry confirmed target engagement, high selectivity, and potency of USP30_inh for USP30 against 49 other deubiquitylating enzymes in a neuroblastoma cell line. In vitro characterization of USP30_inh enzyme kinetics inferred slow and tight binding behavior, which is comparable with features of covalent modification of USP30. Finally, we blended hydrogen–deuterium exchange mass spectrometry and computational docking to elucidate the molecular architecture and geometry of USP30 complex formation with USP30_inh, identifying structural rearrangements at the cleft of the USP30 thumb and palm subdomains. These studies suggest that USP30_inh binds to this thumb–palm cleft, which guides the ubiquitin C terminus into the active site, thereby preventing ubiquitin binding and isopeptide bond cleavage, and confirming its importance in the inhibitory process. Our data will pave the way for the design and development of next-generation inhibitors targeting USP30 and associated deubiquitinylases.

@article{
 title = {Kalirin as a Novel Treatment Target for Cognitive Dysfunction in Schizophrenia.},
 type = {article},
 year = {2022},
 pages = {1-16},
 volume = {36},
 month = {1},
 id = {940c9edd-d258-3539-9426-dc4e55e759a3},
 created = {2022-05-16T07:29:59.213Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2022-05-16T07:29:59.213Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {mould2022kalirinschizophrenia},
 source_type = {article},
 medium = {Print-Electronic},
 private_publication = {false},
 abstract = {The cognitive dysfunction experienced by patients with schizophrenia represents a major unmet clinical need. We believe that enhancing synaptic function and plasticity by targeting kalirin may provide a novel means to remediate these symptoms. Karilin (a protein encoded by the KALRN gene) has multiple functional domains, including two Dbl homology (DH) guanine exchange factor (GEF) domains, which act to enhance the activity of the Rho family guanosine triphosphate (GTP)-ases. Here, we provide an overview of kalirin's roles in brain function and its therapeutic potential in schizophrenia. We outline how it mediates diverse effects via a suite of distinct isoforms that couple to members of the Rho GTPase family to regulate synapse formation and stabilisation, and how genomic and post-mortem data implicate it in schizophrenia. We then review the current state of knowledge about the influence of kalirin on brain function at a systems level, based largely on evidence from transgenic mouse models, which support its proposed role in regulating dendritic spine function and plasticity. We demonstrate that, whilst the GTPases are classically considered to be 'undruggable', targeting kalirin and other Rho GEFs provides a means to indirectly modulate their activity. Finally, we integrate across the information presented to assess the therapeutic potential of kalirin for schizophrenia and highlight the key outstanding questions required to advance it in this capacity; namely, the need for more information about the diversity and function of its isoforms, how these change across neurodevelopment, and how they affect brain function in vivo.},
 bibtype = {article},
 author = {Mould, A W and Al-Juffali, N and von Delft, A and Brennan, P E and Tunbridge, E M},
 doi = {10.1007/s40263-021-00884-z},
 journal = {CNS drugs},
 number = {1}
}

The cognitive dysfunction experienced by patients with schizophrenia represents a major unmet clinical need. We believe that enhancing synaptic function and plasticity by targeting kalirin may provide a novel means to remediate these symptoms. Karilin (a protein encoded by the KALRN gene) has multiple functional domains, including two Dbl homology (DH) guanine exchange factor (GEF) domains, which act to enhance the activity of the Rho family guanosine triphosphate (GTP)-ases. Here, we provide an overview of kalirin's roles in brain function and its therapeutic potential in schizophrenia. We outline how it mediates diverse effects via a suite of distinct isoforms that couple to members of the Rho GTPase family to regulate synapse formation and stabilisation, and how genomic and post-mortem data implicate it in schizophrenia. We then review the current state of knowledge about the influence of kalirin on brain function at a systems level, based largely on evidence from transgenic mouse models, which support its proposed role in regulating dendritic spine function and plasticity. We demonstrate that, whilst the GTPases are classically considered to be 'undruggable', targeting kalirin and other Rho GEFs provides a means to indirectly modulate their activity. Finally, we integrate across the information presented to assess the therapeutic potential of kalirin for schizophrenia and highlight the key outstanding questions required to advance it in this capacity; namely, the need for more information about the diversity and function of its isoforms, how these change across neurodevelopment, and how they affect brain function in vivo.

@article{
 title = {Covalent fragment-based ligand screening approaches for identification of novel ubiquitin proteasome system modulators},
 type = {article},
 year = {2022},
 keywords = {ABPP,E3 ligase,PROTAC,chemoproteomics,covalent fragments,ubiquitin},
 pages = {391-402},
 volume = {403},
 month = {2},
 id = {1ec85c69-2979-3362-9d42-eecc2b93fe91},
 created = {2022-05-16T07:29:59.223Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2022-05-19T11:59:04.778Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {rothweiler2022covalentmodulators},
 source_type = {article},
 medium = {Print-Electronic},
 private_publication = {false},
 abstract = {Ubiquitination is a key regulatory mechanism vital for maintenance of cellular homeostasis. Protein degradation is induced by E3 ligases via attachment of ubiquitin chains to substrates. Pharmacological exploitation of this phenomenon via targeted protein degradation (TPD) can be achieved with molecular glues or bifunctional molecules facilitating the formation of ternary complexes between an E3 ligase and a given protein of interest (POI), resulting in ubiquitination of the substrate and subsequent proteolysis by the proteasome. Recently, the development of novel covalent fragment screening approaches has enabled the identification of first-in-class ligands for E3 ligases and deubiquitinases revealing so far unexplored binding sites which highlights the potential of these methods to uncover and expand druggable space for new target classes.},
 bibtype = {article},
 author = {Rothweiler, Elisabeth M. and Brennan, Paul E. and Huber, Kilian V.M.},
 doi = {10.1515/hsz-2021-0396},
 journal = {Biological Chemistry},
 number = {4}
}

Ubiquitination is a key regulatory mechanism vital for maintenance of cellular homeostasis. Protein degradation is induced by E3 ligases via attachment of ubiquitin chains to substrates. Pharmacological exploitation of this phenomenon via targeted protein degradation (TPD) can be achieved with molecular glues or bifunctional molecules facilitating the formation of ternary complexes between an E3 ligase and a given protein of interest (POI), resulting in ubiquitination of the substrate and subsequent proteolysis by the proteasome. Recently, the development of novel covalent fragment screening approaches has enabled the identification of first-in-class ligands for E3 ligases and deubiquitinases revealing so far unexplored binding sites which highlights the potential of these methods to uncover and expand druggable space for new target classes.

@article{
 title = {Imaging articular cartilage in osteoarthritis using targeted peptide radiocontrast agents.},
 type = {article},
 year = {2022},
 pages = {e0268223},
 volume = {17},
 month = {1},
 id = {bb845ea6-40b7-37f9-862a-dbf7abf1445a},
 created = {2022-05-16T07:30:04.225Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2022-05-16T07:30:04.225Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {fowkes2022imagingagents},
 source_type = {article},
 medium = {Electronic-eCollection},
 private_publication = {false},
 abstract = {<h4>Background</h4>Established MRI and emerging X-ray contrast agents for non-invasive imaging of articular cartilage rely on non-selective electrostatic interactions with negatively charged proteoglycans. These contrast agents have limited prognostic utility in diseases such as osteoarthritis (OA) due to the characteristic high turnover of proteoglycans. To overcome this limitation, we developed a radiocontrast agent that targets the type II collagen macromolecule in cartilage and used it to monitor disease progression in a murine model of OA.<h4>Methods</h4>To confer radiopacity to cartilage contrast agents, the naturally occurring tyrosine derivative 3,5-diiodo-L-tyrosine (DIT) was introduced into a selective peptide for type II collagen. Synthetic DIT peptide derivatives were synthesised by Fmoc-based solid-phase peptide synthesis and binding to ex vivo mouse tibial cartilage evaluated by high-resolution micro-CT. Di-Iodotyrosinated Peptide Imaging of Cartilage (DIPIC) was performed ex vivo and in vivo 4, 8 and 12 weeks in mice after induction of OA by destabilisation of the medial meniscus (DMM). Finally, human osteochondral plugs were imaged ex vivo using DIPIC.<h4>Results</h4>Fifteen DIT peptides were synthesised and tested, yielding seven leads with varying cartilage binding strengths. DIPIC visualised ex vivo murine articular cartilage comparably to the ex vivo contrast agent phosphotungstic acid. Intra-articular injection of contrast agent followed by in vivo DIPIC enabled delineation of damaged murine articular cartilage. Finally, the translational potential of the contrast agent was confirmed by visualisation of ex vivo human cartilage explants.<h4>Conclusion</h4>DIPIC has reduction and refinement implications in OA animal research and potential clinical translation to imaging human disease.},
 bibtype = {article},
 author = {Fowkes, M M and Das Neves Borges, P and Cacho-Nerin, F and Brennan, P E and Vincent, T L and Lim, N H},
 doi = {10.1371/journal.pone.0268223},
 journal = {PloS one},
 number = {5}
}

Background

Established MRI and emerging X-ray contrast agents for non-invasive imaging of articular cartilage rely on non-selective electrostatic interactions with negatively charged proteoglycans. These contrast agents have limited prognostic utility in diseases such as osteoarthritis (OA) due to the characteristic high turnover of proteoglycans. To overcome this limitation, we developed a radiocontrast agent that targets the type II collagen macromolecule in cartilage and used it to monitor disease progression in a murine model of OA.

Methods

To confer radiopacity to cartilage contrast agents, the naturally occurring tyrosine derivative 3,5-diiodo-L-tyrosine (DIT) was introduced into a selective peptide for type II collagen. Synthetic DIT peptide derivatives were synthesised by Fmoc-based solid-phase peptide synthesis and binding to ex vivo mouse tibial cartilage evaluated by high-resolution micro-CT. Di-Iodotyrosinated Peptide Imaging of Cartilage (DIPIC) was performed ex vivo and in vivo 4, 8 and 12 weeks in mice after induction of OA by destabilisation of the medial meniscus (DMM). Finally, human osteochondral plugs were imaged ex vivo using DIPIC.

Results

Fifteen DIT peptides were synthesised and tested, yielding seven leads with varying cartilage binding strengths. DIPIC visualised ex vivo murine articular cartilage comparably to the ex vivo contrast agent phosphotungstic acid. Intra-articular injection of contrast agent followed by in vivo DIPIC enabled delineation of damaged murine articular cartilage. Finally, the translational potential of the contrast agent was confirmed by visualisation of ex vivo human cartilage explants.

Conclusion

DIPIC has reduction and refinement implications in OA animal research and potential clinical translation to imaging human disease.

@article{
 title = {Novel Starting Points for Human Glycolate Oxidase Inhibitors, Revealed by Crystallography-Based Fragment Screening},
 type = {article},
 year = {2022},
 pages = {844598},
 volume = {10},
 websites = {https://www.frontiersin.org/articles/10.3389/fchem.2022.844598/full},
 month = {5},
 day = {4},
 id = {515f8fa5-69fe-3852-8fee-d3c2d827dd1f},
 created = {2023-03-03T13:14:36.581Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2023-04-10T15:38:16.804Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {mackinnon2022novelscreening},
 source_type = {article},
 medium = {Electronic-eCollection},
 private_publication = {false},
 abstract = {Primary hyperoxaluria type I (PH1) is caused by AGXT gene mutations that decrease the functional activity of alanine:glyoxylate aminotransferase. A build-up of the enzyme’s substrate, glyoxylate, results in excessive deposition of calcium oxalate crystals in the renal tract, leading to debilitating renal failure. Oxidation of glycolate by glycolate oxidase (or hydroxy acid oxidase 1, HAO1) is a major cellular source of glyoxylate, and siRNA studies have shown phenotypic rescue of PH1 by the knockdown of HAO1, representing a promising inhibitor target. Here, we report the discovery and optimization of six low-molecular-weight fragments, identified by crystallography-based fragment screening, that bind to two different sites on the HAO1 structure: at the active site and an allosteric pocket above the active site. The active site fragments expand known scaffolds for substrate-mimetic inhibitors to include more chemically attractive molecules. The allosteric fragments represent the first report of non-orthosteric inhibition of any hydroxy acid oxidase and hold significant promise for improving inhibitor selectivity. The fragment hits were verified to bind and inhibit HAO1 in solution by fluorescence-based activity assay and surface plasmon resonance. Further optimization cycle by crystallography and biophysical assays have generated two hit compounds of micromolar (44 and 158 µM) potency that do not compete with the substrate and provide attractive starting points for the development of potent and selective HAO1 inhibitors.},
 bibtype = {article},
 author = {Mackinnon, Sabrina R and Bezerra, Gustavo A and Krojer, Tobias and Szommer, Tamas and von Delft, Frank and Brennan, Paul E and Yue, Wyatt W},
 doi = {10.3389/fchem.2022.844598},
 journal = {Frontiers in Chemistry}
}

Primary hyperoxaluria type I (PH1) is caused by AGXT gene mutations that decrease the functional activity of alanine:glyoxylate aminotransferase. A build-up of the enzyme’s substrate, glyoxylate, results in excessive deposition of calcium oxalate crystals in the renal tract, leading to debilitating renal failure. Oxidation of glycolate by glycolate oxidase (or hydroxy acid oxidase 1, HAO1) is a major cellular source of glyoxylate, and siRNA studies have shown phenotypic rescue of PH1 by the knockdown of HAO1, representing a promising inhibitor target. Here, we report the discovery and optimization of six low-molecular-weight fragments, identified by crystallography-based fragment screening, that bind to two different sites on the HAO1 structure: at the active site and an allosteric pocket above the active site. The active site fragments expand known scaffolds for substrate-mimetic inhibitors to include more chemically attractive molecules. The allosteric fragments represent the first report of non-orthosteric inhibition of any hydroxy acid oxidase and hold significant promise for improving inhibitor selectivity. The fragment hits were verified to bind and inhibit HAO1 in solution by fluorescence-based activity assay and surface plasmon resonance. Further optimization cycle by crystallography and biophysical assays have generated two hit compounds of micromolar (44 and 158 µM) potency that do not compete with the substrate and provide attractive starting points for the development of potent and selective HAO1 inhibitors.

@article{
 title = {Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane},
 type = {article},
 year = {2022},
 keywords = {Drug discovery and development,Synthetic chemistry methodology},
 pages = {721-726},
 volume = {611},
 websites = {https://www.nature.com/articles/s41586-022-05290-z},
 month = {9},
 publisher = {Nature Publishing Group},
 day = {15},
 id = {c573c773-1c99-38e9-b57e-294d0b721e92},
 created = {2023-05-14T11:56:16.346Z},
 accessed = {2023-05-14},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2023-05-16T12:56:54.295Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly found para-substituted benzene rings in drug design1. The utility of these cage structures derives from their superior pharmacokinetic properties compared with their parent aromatics, including improved solubility and reduced susceptibility to metabolism2,3. A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesized by ring-opening of the interbridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions4. By contrast, scaffolds mimicking meta-substituted arenes are lacking because of the challenge of synthesizing saturated isosteres that accurately reproduce substituent vectors5. Here we show that bicyclo[3.1.1]heptanes (BCHeps), which are hydrocarbons for which the bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on a multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of the absorption, distribution, metabolism and excretion (ADME) properties of these analogues reveals enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta-arene analogue as an sp3-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a new surrogate for meta-substituted benzene rings for implementation in drug discovery programmes. The potential power of the saturated carbocycle bicyclo[3.1.1]heptane as a beneficial motif for improving the pharmacokinetic and physicochemical properties of drug candidates is demonstrated.},
 bibtype = {article},
 author = {Frank, Nils and Nugent, Jeremy and Shire, Bethany R. and Pickford, Helena D. and Rabe, Patrick and Sterling, Alistair J. and Zarganes-Tzitzikas, Tryfon and Grimes, Thomas and Thompson, Amber L. and Smith, Russell C. and Schofield, Christopher J. and Brennan, Paul E. and Duarte, Fernanda and Anderson, Edward A.},
 doi = {10.1038/s41586-022-05290-z},
 journal = {Nature 2022 611:7937},
 number = {7937}
}

Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly found para-substituted benzene rings in drug design1. The utility of these cage structures derives from their superior pharmacokinetic properties compared with their parent aromatics, including improved solubility and reduced susceptibility to metabolism2,3. A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesized by ring-opening of the interbridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions4. By contrast, scaffolds mimicking meta-substituted arenes are lacking because of the challenge of synthesizing saturated isosteres that accurately reproduce substituent vectors5. Here we show that bicyclo[3.1.1]heptanes (BCHeps), which are hydrocarbons for which the bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on a multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of the absorption, distribution, metabolism and excretion (ADME) properties of these analogues reveals enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta-arene analogue as an sp3-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a new surrogate for meta-substituted benzene rings for implementation in drug discovery programmes. The potential power of the saturated carbocycle bicyclo[3.1.1]heptane as a beneficial motif for improving the pharmacokinetic and physicochemical properties of drug candidates is demonstrated.

@article{
 title = {Imaging articular cartilage in osteoarthritis using targeted peptide radiocontrast agents},
 type = {article},
 year = {2022},
 keywords = {Articular cartilage,Cartilage,Collagens,In vivo imaging,Magnetic resonance imaging,Osteoarthritis,Tibia,X-ray radiography},
 pages = {e0268223},
 volume = {17},
 websites = {https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0268223},
 month = {5},
 publisher = {Public Library of Science},
 day = {1},
 id = {0104c2ba-950f-3511-8a4a-a3f2c89e07ea},
 created = {2023-05-14T11:56:31.727Z},
 accessed = {2023-05-14},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2023-05-16T12:56:53.998Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {Background Established MRI and emerging X-ray contrast agents for non-invasive imaging of articular cartilage rely on non-selective electrostatic interactions with negatively charged proteoglycans. These contrast agents have limited prognostic utility in diseases such as osteoarthritis (OA) due to the characteristic high turnover of proteoglycans. To overcome this limitation, we developed a radiocontrast agent that targets the type II collagen macromolecule in cartilage and used it to monitor disease progression in a murine model of OA.   Methods To confer radiopacity to cartilage contrast agents, the naturally occurring tyrosine derivative 3,5-diiodo-L-tyrosine (DIT) was introduced into a selective peptide for type II collagen. Synthetic DIT peptide derivatives were synthesised by Fmoc-based solid-phase peptide synthesis and binding to ex vivo mouse tibial cartilage evaluated by high-resolution micro-CT. Di-Iodotyrosinated Peptide Imaging of Cartilage (DIPIC) was performed ex vivo and in vivo 4, 8 and 12 weeks in mice after induction of OA by destabilisation of the medial meniscus (DMM). Finally, human osteochondral plugs were imaged ex vivo using DIPIC.   Results Fifteen DIT peptides were synthesised and tested, yielding seven leads with varying cartilage binding strengths. DIPIC visualised ex vivo murine articular cartilage comparably to the ex vivo contrast agent phosphotungstic acid. Intra-articular injection of contrast agent followed by in vivo DIPIC enabled delineation of damaged murine articular cartilage. Finally, the translational potential of the contrast agent was confirmed by visualisation of ex vivo human cartilage explants.   Conclusion DIPIC has reduction and refinement implications in OA animal research and potential clinical translation to imaging human disease.},
 bibtype = {article},
 author = {Fowkes, Milan M. and Borges, Patricia Das Neves and Cacho-Nerin, Fernando and Brennan, Paul E. and Vincent, Tonia L. and Lim, Ngee H.},
 doi = {10.1371/JOURNAL.PONE.0268223},
 journal = {PLOS ONE},
 number = {5}
}

Background Established MRI and emerging X-ray contrast agents for non-invasive imaging of articular cartilage rely on non-selective electrostatic interactions with negatively charged proteoglycans. These contrast agents have limited prognostic utility in diseases such as osteoarthritis (OA) due to the characteristic high turnover of proteoglycans. To overcome this limitation, we developed a radiocontrast agent that targets the type II collagen macromolecule in cartilage and used it to monitor disease progression in a murine model of OA. Methods To confer radiopacity to cartilage contrast agents, the naturally occurring tyrosine derivative 3,5-diiodo-L-tyrosine (DIT) was introduced into a selective peptide for type II collagen. Synthetic DIT peptide derivatives were synthesised by Fmoc-based solid-phase peptide synthesis and binding to ex vivo mouse tibial cartilage evaluated by high-resolution micro-CT. Di-Iodotyrosinated Peptide Imaging of Cartilage (DIPIC) was performed ex vivo and in vivo 4, 8 and 12 weeks in mice after induction of OA by destabilisation of the medial meniscus (DMM). Finally, human osteochondral plugs were imaged ex vivo using DIPIC. Results Fifteen DIT peptides were synthesised and tested, yielding seven leads with varying cartilage binding strengths. DIPIC visualised ex vivo murine articular cartilage comparably to the ex vivo contrast agent phosphotungstic acid. Intra-articular injection of contrast agent followed by in vivo DIPIC enabled delineation of damaged murine articular cartilage. Finally, the translational potential of the contrast agent was confirmed by visualisation of ex vivo human cartilage explants. Conclusion DIPIC has reduction and refinement implications in OA animal research and potential clinical translation to imaging human disease.

@article{
 title = {Novel Starting Points for Human Glycolate Oxidase Inhibitors, Revealed by Crystallography-Based Fragment Screening},
 type = {article},
 year = {2022},
 keywords = {fragment-based drug discovery,glycolate oxidase,glyoxylate metabolism,primary hyperoxaluria,substrate reduction therapy},
 pages = {345},
 volume = {10},
 month = {5},
 publisher = {Frontiers Media S.A.},
 day = {4},
 id = {862cc5ca-3189-3637-b90d-2072b449c0ab},
 created = {2023-05-14T11:56:59.283Z},
 accessed = {2023-05-14},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2023-05-16T12:56:54.498Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {Primary hyperoxaluria type I (PH1) is caused by AGXT gene mutations that decrease the functional activity of alanine:glyoxylate aminotransferase. A build-up of the enzyme’s substrate, glyoxylate, results in excessive deposition of calcium oxalate crystals in the renal tract, leading to debilitating renal failure. Oxidation of glycolate by glycolate oxidase (or hydroxy acid oxidase 1, HAO1) is a major cellular source of glyoxylate, and siRNA studies have shown phenotypic rescue of PH1 by the knockdown of HAO1, representing a promising inhibitor target. Here, we report the discovery and optimization of six low-molecular-weight fragments, identified by crystallography-based fragment screening, that bind to two different sites on the HAO1 structure: at the active site and an allosteric pocket above the active site. The active site fragments expand known scaffolds for substrate-mimetic inhibitors to include more chemically attractive molecules. The allosteric fragments represent the first report of non-orthosteric inhibition of any hydroxy acid oxidase and hold significant promise for improving inhibitor selectivity. The fragment hits were verified to bind and inhibit HAO1 in solution by fluorescence-based activity assay and surface plasmon resonance. Further optimization cycle by crystallography and biophysical assays have generated two hit compounds of micromolar (44 and 158 µM) potency that do not compete with the substrate and provide attractive starting points for the development of potent and selective HAO1 inhibitors.},
 bibtype = {article},
 author = {Mackinnon, Sabrina R. and Bezerra, Gustavo A. and Krojer, Tobias and Szommer, Tamas and von Delft, Frank and Brennan, Paul E. and Yue, Wyatt W.},
 doi = {10.3389/FCHEM.2022.844598/BIBTEX},
 journal = {Frontiers in Chemistry}
}

Primary hyperoxaluria type I (PH1) is caused by AGXT gene mutations that decrease the functional activity of alanine:glyoxylate aminotransferase. A build-up of the enzyme’s substrate, glyoxylate, results in excessive deposition of calcium oxalate crystals in the renal tract, leading to debilitating renal failure. Oxidation of glycolate by glycolate oxidase (or hydroxy acid oxidase 1, HAO1) is a major cellular source of glyoxylate, and siRNA studies have shown phenotypic rescue of PH1 by the knockdown of HAO1, representing a promising inhibitor target. Here, we report the discovery and optimization of six low-molecular-weight fragments, identified by crystallography-based fragment screening, that bind to two different sites on the HAO1 structure: at the active site and an allosteric pocket above the active site. The active site fragments expand known scaffolds for substrate-mimetic inhibitors to include more chemically attractive molecules. The allosteric fragments represent the first report of non-orthosteric inhibition of any hydroxy acid oxidase and hold significant promise for improving inhibitor selectivity. The fragment hits were verified to bind and inhibit HAO1 in solution by fluorescence-based activity assay and surface plasmon resonance. Further optimization cycle by crystallography and biophysical assays have generated two hit compounds of micromolar (44 and 158 µM) potency that do not compete with the substrate and provide attractive starting points for the development of potent and selective HAO1 inhibitors.

@article{
 title = {Male sex chromosomal complement exacerbates the pathogenicity of Th17 cells in a chronic model of central nervous system autoimmunity.},
 type = {article},
 year = {2021},
 pages = {108833},
 volume = {34},
 month = {3},
 id = {e70fda24-54e3-3f3f-a18d-54b938913577},
 created = {2021-04-28T15:28:54.874Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2021-04-28T15:28:54.874Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {doss2021maleautoimmunity},
 source_type = {article},
 medium = {Print},
 private_publication = {false},
 abstract = {Sex differences in multiple sclerosis (MS) incidence and severity have long been recognized. However, the underlying cellular and molecular mechanisms for why male sex is associated with more aggressive disease remain poorly defined. Using a T cell adoptive transfer model of chronic experimental autoimmune encephalomyelitis (EAE), we find that male Th17 cells induce disease of increased severity relative to female Th17 cells, irrespective of whether transferred to male or female recipients. Throughout the disease course, a greater frequency of male Th17 cells produce IFNγ, a hallmark of pathogenic Th17 responses. Intriguingly, XY chromosomal complement increases the pathogenicity of male Th17 cells. An X-linked immune regulator, Jarid1c, is downregulated in pathogenic male murine Th17 cells, and functional experiments reveal that it represses the severity of Th17-mediated EAE. Furthermore, Jarid1c expression is downregulated in CD4<sup>+</sup> T cells from MS-affected individuals. Our data indicate that male sex chromosomal complement critically regulates Th17 cell pathogenicity.},
 bibtype = {article},
 author = {Doss, PMIA and Umair, M and Baillargeon, J and Fazazi, R and Fudge, N and Akbar, I and Yeola, A P and Williams, J B and Leclercq, M and Joly-Beauparlant, C and Beauchemin, P and Ruda, G F and Alpaugh, M and Anderson, A C and Brennan, P E and Droit, A and Lassmann, H and Moore, C S and Rangachari, M},
 doi = {10.1016/j.celrep.2021.108833},
 journal = {Cell reports},
 number = {10}
}

Sex differences in multiple sclerosis (MS) incidence and severity have long been recognized. However, the underlying cellular and molecular mechanisms for why male sex is associated with more aggressive disease remain poorly defined. Using a T cell adoptive transfer model of chronic experimental autoimmune encephalomyelitis (EAE), we find that male Th17 cells induce disease of increased severity relative to female Th17 cells, irrespective of whether transferred to male or female recipients. Throughout the disease course, a greater frequency of male Th17 cells produce IFNγ, a hallmark of pathogenic Th17 responses. Intriguingly, XY chromosomal complement increases the pathogenicity of male Th17 cells. An X-linked immune regulator, Jarid1c, is downregulated in pathogenic male murine Th17 cells, and functional experiments reveal that it represses the severity of Th17-mediated EAE. Furthermore, Jarid1c expression is downregulated in CD4⁺ T cells from MS-affected individuals. Our data indicate that male sex chromosomal complement critically regulates Th17 cell pathogenicity.

@article{
 title = {Chemogenomics for drug discovery: Clinical molecules from open access chemical probes},
 type = {article},
 year = {2021},
 pages = {759-795},
 volume = {2},
 publisher = {Royal Society of Chemistry (RSC)},
 id = {a2f5c249-1411-30c4-addf-b330a74bcc3f},
 created = {2021-04-28T15:28:54.966Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2024-04-08T14:07:30.951Z},
 read = {true},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {quinlanchemogenomicsprobes},
 source_type = {article},
 private_publication = {false},
 abstract = {In recent years chemical probes have proved valuable tools for the validation of disease-modifying targets, facilitating investigation of target function, safety, and translation. Whilst probes and drugs often differ in their properties, there is a belief that chemical probes are useful for translational studies and can accelerate the drug discovery process by providing a starting point for small molecule drugs. This review seeks to describe clinical candidates that have been inspired by, or derived from, chemical probes, and the process behind their development. By focusing primarily on examples of probes developed by the Structural Genomics Consortium, we examine a variety of epigenetic modulators along with other classes of probe. This journal is},
 bibtype = {article},
 author = {Quinlan, Robert B.A. and Brennan, Paul E.},
 doi = {10.1039/d1cb00016k},
 journal = {RSC Chemical Biology},
 number = {3}
}

In recent years chemical probes have proved valuable tools for the validation of disease-modifying targets, facilitating investigation of target function, safety, and translation. Whilst probes and drugs often differ in their properties, there is a belief that chemical probes are useful for translational studies and can accelerate the drug discovery process by providing a starting point for small molecule drugs. This review seeks to describe clinical candidates that have been inspired by, or derived from, chemical probes, and the process behind their development. By focusing primarily on examples of probes developed by the Structural Genomics Consortium, we examine a variety of epigenetic modulators along with other classes of probe. This journal is

@article{
 title = {Fragment Screening Reveals Starting Points for Rational Design of Galactokinase 1 Inhibitors to Treat Classic Galactosemia.},
 type = {article},
 year = {2021},
 pages = {586-595},
 volume = {16},
 month = {4},
 id = {9e1aaf21-f61e-3ad2-a1e8-8cd09572e698},
 created = {2021-04-28T15:28:54.970Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2021-04-28T15:28:54.970Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {mackinnon2021fragmentgalactosemia},
 source_type = {article},
 medium = {Print-Electronic},
 private_publication = {false},
 abstract = {Classic galactosemia is caused by loss-of-function mutations in galactose-1-phosphate uridylyltransferase (GALT) that lead to toxic accumulation of its substrate, galactose-1-phosphate. One proposed therapy is to inhibit the biosynthesis of galactose-1-phosphate, catalyzed by galactokinase 1 (GALK1). Existing inhibitors of human GALK1 (hGALK1) are primarily ATP-competitive with limited clinical utility to date. Here, we determined crystal structures of hGALK1 bound with reported ATP-competitive inhibitors of the spiro-benzoxazole series, to reveal their binding mode in the active site. Spurred by the need for additional chemotypes of hGALK1 inhibitors, desirably targeting a nonorthosteric site, we also performed crystallography-based screening by soaking hundreds of hGALK1 crystals, already containing active site ligands, with fragments from a custom library. Two fragments were found to bind close to the ATP binding site, and a further eight were found in a hotspot distal from the active site, highlighting the strength of this method in identifying previously uncharacterized allosteric sites. To generate inhibitors of improved potency and selectivity targeting the newly identified binding hotspot, new compounds were designed by merging overlapping fragments. This yielded two micromolar inhibitors of hGALK1 that were not competitive with respect to either substrate (ATP or galactose) and demonstrated good selectivity over hGALK1 homologues, galactokinase 2 and mevalonate kinase. Our findings are therefore the first to demonstrate inhibition of hGALK1 from an allosteric site, with potential for further development of potent and selective inhibitors to provide novel therapeutics for classic galactosemia.},
 bibtype = {article},
 author = {Mackinnon, S R and Krojer, T and Foster, W R and Diaz-Saez, L and Tang, M and Huber, K V M and von Delft, F and Lai, K and Brennan, P E and Arruda Bezerra, G and Yue, W W},
 doi = {10.1021/acschembio.0c00498},
 journal = {ACS chemical biology},
 number = {4}
}

Classic galactosemia is caused by loss-of-function mutations in galactose-1-phosphate uridylyltransferase (GALT) that lead to toxic accumulation of its substrate, galactose-1-phosphate. One proposed therapy is to inhibit the biosynthesis of galactose-1-phosphate, catalyzed by galactokinase 1 (GALK1). Existing inhibitors of human GALK1 (hGALK1) are primarily ATP-competitive with limited clinical utility to date. Here, we determined crystal structures of hGALK1 bound with reported ATP-competitive inhibitors of the spiro-benzoxazole series, to reveal their binding mode in the active site. Spurred by the need for additional chemotypes of hGALK1 inhibitors, desirably targeting a nonorthosteric site, we also performed crystallography-based screening by soaking hundreds of hGALK1 crystals, already containing active site ligands, with fragments from a custom library. Two fragments were found to bind close to the ATP binding site, and a further eight were found in a hotspot distal from the active site, highlighting the strength of this method in identifying previously uncharacterized allosteric sites. To generate inhibitors of improved potency and selectivity targeting the newly identified binding hotspot, new compounds were designed by merging overlapping fragments. This yielded two micromolar inhibitors of hGALK1 that were not competitive with respect to either substrate (ATP or galactose) and demonstrated good selectivity over hGALK1 homologues, galactokinase 2 and mevalonate kinase. Our findings are therefore the first to demonstrate inhibition of hGALK1 from an allosteric site, with potential for further development of potent and selective inhibitors to provide novel therapeutics for classic galactosemia.

@article{
 title = {RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors},
 type = {article},
 year = {2021},
 keywords = {Ras homologous (RHO) small GTPases,cell signaling,dedicator of cytokinesis (DOCK),drug discovery,guanine nucleotide exchange factor,guanosine triphosphate (GTP),structural biology},
 pages = {100521},
 volume = {296},
 websites = {https://doi.org/10.1016/j.jbc.2021.100521},
 month = {1},
 publisher = {Elsevier BV},
 day = {1},
 id = {34ffac7a-6624-3eec-a4b3-47154bb87399},
 created = {2021-05-04T13:12:49.630Z},
 accessed = {2021-05-04},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2024-04-10T13:32:02.140Z},
 read = {true},
 starred = {true},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.},
 bibtype = {article},
 author = {Thompson, Andrew P. and Bitsina, Christina and Gray, Janine L. and von Delft, Frank and Brennan, Paul E.},
 doi = {10.1016/j.jbc.2021.100521},
 journal = {Journal of Biological Chemistry}
}

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

@article{
 title = {A phenotypic high-content, high-throughput screen identifies inhibitors of NLRP3 inflammasome activation.},
 type = {article},
 year = {2021},
 pages = {15319},
 volume = {11},
 month = {7},
 id = {9f8d1948-dfc9-3d08-8a0a-7ea10535dbd3},
 created = {2021-09-06T13:36:55.958Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2022-05-13T08:55:37.356Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {nizami2021aactivation},
 source_type = {article},
 medium = {Electronic},
 folder_uuids = {e9955300-9da8-4e03-932d-0db29af93f78},
 private_publication = {false},
 abstract = {Inhibition of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome has recently emerged as a promising therapeutic target for several inflammatory diseases. After priming and activation by inflammation triggers, NLRP3 forms a complex with apoptosis-associated speck-like protein containing a CARD domain (ASC) followed by formation of the active inflammasome. Identification of inhibitors of NLRP3 activation requires a well-validated primary high-throughput assay followed by the deployment of a screening cascade of assays enabling studies of structure-activity relationship, compound selectivity and efficacy in disease models. We optimized a NLRP3-dependent fluorescent tagged ASC speck formation assay in murine immortalized bone marrow-derived macrophages and utilized it to screen a compound library of 81,000 small molecules. Our high-content screening assay yielded robust assay metrics and identified a number of inhibitors of NLRP3-dependent ASC speck formation, including compounds targeting HSP90, JAK and IKK-β. Additional assays to investigate inflammasome priming or activation, NLRP3 downstream effectors such as caspase-1, IL-1β and pyroptosis form the basis of a screening cascade to identify NLRP3 inflammasome inhibitors in drug discovery programs.},
 bibtype = {article},
 author = {Nizami, S and Millar, V and Arunasalam, K and Zarganes-Tzitzikas, T and Brough, D and Tresadern, G and Brennan, P E and Davis, J B and Ebner, D and Di Daniel, E},
 doi = {10.1038/s41598-021-94850-w},
 journal = {Scientific reports},
 number = {1}
}

Inhibition of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome has recently emerged as a promising therapeutic target for several inflammatory diseases. After priming and activation by inflammation triggers, NLRP3 forms a complex with apoptosis-associated speck-like protein containing a CARD domain (ASC) followed by formation of the active inflammasome. Identification of inhibitors of NLRP3 activation requires a well-validated primary high-throughput assay followed by the deployment of a screening cascade of assays enabling studies of structure-activity relationship, compound selectivity and efficacy in disease models. We optimized a NLRP3-dependent fluorescent tagged ASC speck formation assay in murine immortalized bone marrow-derived macrophages and utilized it to screen a compound library of 81,000 small molecules. Our high-content screening assay yielded robust assay metrics and identified a number of inhibitors of NLRP3-dependent ASC speck formation, including compounds targeting HSP90, JAK and IKK-β. Additional assays to investigate inflammasome priming or activation, NLRP3 downstream effectors such as caspase-1, IL-1β and pyroptosis form the basis of a screening cascade to identify NLRP3 inflammasome inhibitors in drug discovery programs.

@article{
 title = {The structural basis of fatty acid elongation by the ELOVL elongases},
 type = {article},
 year = {2021},
 pages = {512-520},
 volume = {28},
 month = {6},
 publisher = {Nature Research},
 id = {666d099b-7d9a-3963-884b-ffb252a01cc4},
 created = {2021-09-06T13:36:55.967Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2021-09-06T13:36:55.967Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {nie2021theelongases},
 source_type = {article},
 private_publication = {false},
 abstract = {Very long chain fatty acids (VLCFAs) are essential building blocks for the synthesis of ceramides and sphingolipids. The first step in the fatty acid elongation cycle is catalyzed by the 3-keto acyl-coenzyme A (CoA) synthases (in mammals, ELOVL elongases). Although ELOVLs are implicated in common diseases, including insulin resistance, hepatic steatosis and Parkinson’s, their underlying molecular mechanisms are unknown. Here we report the structure of the human ELOVL7 elongase, which comprises an inverted transmembrane barrel surrounding a 35-Å long tunnel containing a covalently attached product analogue. The structure reveals the substrate-binding sites in the narrow tunnel and an active site deep in the membrane. We demonstrate that chain elongation proceeds via an acyl-enzyme intermediate involving the second histidine in the canonical HxxHH motif. The unusual substrate-binding arrangement and chemistry suggest mechanisms for selective ELOVL inhibition, relevant for diseases where VLCFAs accumulate, such as X-linked adrenoleukodystrophy.

},
 bibtype = {article},
 author = {Nie, L and Pascoa, T C and Pike, A C W and Bushell, S R and Quigley, A and Ruda, G F and Chu, A and Cole, V and Speedman, D and Moreira, T and Shrestha, L and Mukhopadhyay, S M M and Burgess-Brown, N A and Love, J D and Brennan, P E and Carpenter, E P},
 doi = {10.1038/s41594-021-00605-6},
 journal = {Nature Structural and Molecular Biology},
 number = {6}
}

Very long chain fatty acids (VLCFAs) are essential building blocks for the synthesis of ceramides and sphingolipids. The first step in the fatty acid elongation cycle is catalyzed by the 3-keto acyl-coenzyme A (CoA) synthases (in mammals, ELOVL elongases). Although ELOVLs are implicated in common diseases, including insulin resistance, hepatic steatosis and Parkinson’s, their underlying molecular mechanisms are unknown. Here we report the structure of the human ELOVL7 elongase, which comprises an inverted transmembrane barrel surrounding a 35-Å long tunnel containing a covalently attached product analogue. The structure reveals the substrate-binding sites in the narrow tunnel and an active site deep in the membrane. We demonstrate that chain elongation proceeds via an acyl-enzyme intermediate involving the second histidine in the canonical HxxHH motif. The unusual substrate-binding arrangement and chemistry suggest mechanisms for selective ELOVL inhibition, relevant for diseases where VLCFAs accumulate, such as X-linked adrenoleukodystrophy.

@inproceedings{
 title = {Combinatorial library screening for selective ADAMTS-5 peptide substrates to study aggrecanase activity},
 type = {inproceedings},
 year = {2021},
 pages = {A11--A12},
 volume = {102},
 issue = {4-5},
 websites = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2%5C&SrcApp=PARTNER_APP%5C&SrcAuth=LinksAMR%5C&KeyUT=WOS:000715825800023%5C&DestLinkType=FullRecord%5C&DestApp=ALL_WOS%5C&UsrCustomerID=4fd6f7d59a501f9b8bac2be37914c43e},
 month = {8},
 id = {8ef07d00-45fb-38fa-9431-98f03795ce93},
 created = {2022-05-16T07:29:59.320Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2022-05-16T07:29:59.320Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {fowkes2021combinatorialactivity},
 source_type = {inproceedings},
 private_publication = {false},
 bibtype = {inproceedings},
 author = {Fowkes, M M and Vincent, T L and Brennan, P E and Meldal, M and Lim, N H},
 booktitle = {Int J Exp Pathol}
}

@article{
 title = {Target 2035-update on the quest for a probe for every protein},
 type = {article},
 year = {2021},
 pages = {13-21},
 volume = {13},
 month = {12},
 publisher = {Royal Society of Chemistry},
 id = {e47fe21b-a938-386f-a878-bd0354040511},
 created = {2022-05-16T07:29:59.438Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2022-05-16T07:29:59.438Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {alchawaf2021targetprotein},
 source_type = {article},
 private_publication = {false},
 abstract = {Twenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. The challenge of translating the wealth of new knowledge from genomics into new medicines is that proteins, and not genes, are the primary executers of biological function. Therefore, much of how biology works in health and disease must be understood through the lens of protein function. Accordingly, a subset of human proteins has been at the heart of research interests of scientists over the centuries, and we have accumulated varying degrees of knowledge about approximately 65\% of the human proteome. Nevertheless, a large proportion of proteins in the human proteome (∼35\%) remains uncharacterized, and less than 5\% of the human proteome has been successfully targeted for drug discovery. This highlights the profound disconnect between our abilities to obtain genetic information and subsequent development of effective medicines. Target 2035 is an international federation of biomedical scientists from the public and private sectors, which aims to address this gap by developing and applying new technologies to create by year 2035 chemogenomic libraries, chemical probes, and/or biological probes for the entire human proteome.},
 bibtype = {article},
 author = {Al Chawaf, A and Bullock, A N and Carter, A J and Chaikuad, A and Chaineau, M and Ciulli, A and Collins, I and Dreher, J and Drewry, D and Edfeldt, K and Edwards, A M and Egner, U and Frye, S V and Fuchs, S M and Hall, M D and Hartung, I V and Hillisch, A and Hitchcock, S H and Kannan, N and Kiefer, J R and Knapp, S and Morgan, M R and Rosenberg, S H and Saikatendu, K S and Schapira, M},
 doi = {10.1039/d1md00228g},
 journal = {RSC Medicinal Chemistry},
 number = {1}
}

Twenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. The challenge of translating the wealth of new knowledge from genomics into new medicines is that proteins, and not genes, are the primary executers of biological function. Therefore, much of how biology works in health and disease must be understood through the lens of protein function. Accordingly, a subset of human proteins has been at the heart of research interests of scientists over the centuries, and we have accumulated varying degrees of knowledge about approximately 65\% of the human proteome. Nevertheless, a large proportion of proteins in the human proteome (∼35\%) remains uncharacterized, and less than 5\% of the human proteome has been successfully targeted for drug discovery. This highlights the profound disconnect between our abilities to obtain genetic information and subsequent development of effective medicines. Target 2035 is an international federation of biomedical scientists from the public and private sectors, which aims to address this gap by developing and applying new technologies to create by year 2035 chemogenomic libraries, chemical probes, and/or biological probes for the entire human proteome.

@misc{
 title = {N-substituted-3,4-(fused 5-ring)-5-phenyl-pyrrolidine-2-one compounds as inhibitors of isoQC and/or QC enzyme},
 type = {misc},
 year = {2021},
 source = {World Intellectual Property Organization},
 keywords = {phenylpyrrolidinone preparation isoQC QC inhibitor cancer atherosclerosis fibrosis infection},
 issue = {WO2021009068},
 month = {1},
 publisher = {Scenic Immunology B.V.},
 day = {21},
 id = {1be3ff0d-ace2-3c59-9558-d060894b55e9},
 created = {2024-05-14T09:38:28.783Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2024-05-14T09:41:21.874Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 source_type = {PAT},
 notes = {WO2021009068 A1},
 private_publication = {false},
 abstract = {The present invention pertains generally to the field of therapeutic compounds The invention relates to N-substituted-3,4-(fused 5-ring)-5-phenyl-pyrrolidin-2-one compounds of formula I (also referred to herein as "FRPPO compounds"), that, inter alia, inhibit glutaminyl-peptide cyclotransferase-like (isoQC) enzyme and/or glutaminyl-peptide cyclotransferase (QC) enzyme (e.g., inhibit or reduce or block the activity or function of isoQC and/or QC enzyme). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit isoQC and/or QC enzyme; to treat disorders that are ameliorated by the inhibition of isoQC and/or QC enzyme; to treat cancer, atherosclerosis, fibrotic diseases, infectious diseases, etc. Compounds of formula I wherein ring A is 5-membered heteroaromatic; Q is substituted benzimidazolyl, substituted imidazopyridinyl, J is substituted Ph, and pharmaceutically acceptable salts, hydrates, and solvates thereof, are claimed. Example compound II was prepared by a multistep procedure (procedure given). The invention compounds were evaluated for their isoQC and QC inhibitory activities (some data given).},
 bibtype = {misc},
 author = {Evers, Bastiaan and Brennan, Paul E}
}

The present invention pertains generally to the field of therapeutic compounds The invention relates to N-substituted-3,4-(fused 5-ring)-5-phenyl-pyrrolidin-2-one compounds of formula I (also referred to herein as "FRPPO compounds"), that, inter alia, inhibit glutaminyl-peptide cyclotransferase-like (isoQC) enzyme and/or glutaminyl-peptide cyclotransferase (QC) enzyme (e.g., inhibit or reduce or block the activity or function of isoQC and/or QC enzyme). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit isoQC and/or QC enzyme; to treat disorders that are ameliorated by the inhibition of isoQC and/or QC enzyme; to treat cancer, atherosclerosis, fibrotic diseases, infectious diseases, etc. Compounds of formula I wherein ring A is 5-membered heteroaromatic; Q is substituted benzimidazolyl, substituted imidazopyridinyl, J is substituted Ph, and pharmaceutically acceptable salts, hydrates, and solvates thereof, are claimed. Example compound II was prepared by a multistep procedure (procedure given). The invention compounds were evaluated for their isoQC and QC inhibitory activities (some data given).

@misc{
 title = {Targeting the Small GTPase Superfamily through Their Regulatory Proteins},
 type = {misc},
 year = {2020},
 source = {Angewandte Chemie - International Edition},
 keywords = {drug discovery,peptides,protein–protein interactions,small GTPases,small molecules},
 pages = {6342-6366},
 volume = {59},
 issue = {16},
 websites = {http://doi.wiley.com/10.1002/anie.201900585},
 month = {3},
 publisher = {John Wiley & Sons, Ltd},
 day = {14},
 id = {70da69b4-7ccd-3681-bf0b-980af4e0a25f},
 created = {2019-04-25T07:11:04.302Z},
 accessed = {2019-04-25},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2024-05-03T15:20:00.958Z},
 read = {true},
 starred = {true},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 citation_key = {Gray2019},
 folder_uuids = {5358531d-d036-484b-937b-88c0f1ef606b},
 private_publication = {false},
 abstract = {The Ras superfamily of small GTPases are guanine-nucleotide-dependent switches essential for numerous cellular processes. Mutations or dysregulation of these proteins are associated with many diseases, but unsuccessful attempts to target the small GTPases directly have resulted in them being classed as “undruggable”. The GTP-dependent signaling of these proteins is controlled by their regulators; guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and in the Rho and Rab subfamilies, guanine nucleotide dissociation inhibitors (GDIs). This review covers the recent small molecule and biologics strategies to target the small GTPases through their regulators. It seeks to critically re-evaluate recent chemical biology practice, such as the presence of PAINs motifs and the cell-based readout using compounds that are weakly potent or of unknown specificity. It highlights the vast scope of potential approaches for targeting the small GTPases in the future through their regulatory proteins.},
 bibtype = {misc},
 author = {Gray, Janine L. and von Delft, Frank and Brennan, Paul E.},
 doi = {10.1002/anie.201900585}
}

The Ras superfamily of small GTPases are guanine-nucleotide-dependent switches essential for numerous cellular processes. Mutations or dysregulation of these proteins are associated with many diseases, but unsuccessful attempts to target the small GTPases directly have resulted in them being classed as “undruggable”. The GTP-dependent signaling of these proteins is controlled by their regulators; guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and in the Rho and Rab subfamilies, guanine nucleotide dissociation inhibitors (GDIs). This review covers the recent small molecule and biologics strategies to target the small GTPases through their regulators. It seeks to critically re-evaluate recent chemical biology practice, such as the presence of PAINs motifs and the cell-based readout using compounds that are weakly potent or of unknown specificity. It highlights the vast scope of potential approaches for targeting the small GTPases in the future through their regulatory proteins.

@article{
 title = {TargetDB: A target information aggregation tool and tractability predictor},
 type = {article},
 year = {2020},
 pages = {2020.04.21.052878},
 websites = {http://biorxiv.org/content/early/2020/04/21/2020.04.21.052878.abstract},
 month = {1},
 day = {1},
 id = {8e5e073c-5503-350c-a493-d6f0b481380c},
 created = {2020-08-18T17:56:43.700Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2020-08-18T17:56:43.700Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 source_type = {JOUR},
 private_publication = {false},
 abstract = {When trying to identify new potential therapeutic targets, access to data and knowledge is increasingly important. In a field where new resources and data sources become available every day, it is crucial to be able to take a step back and look at the wider picture in order to identify potential drug targets. While this task is routinely performed by bespoke researchers, it is often time-consuming and lacks uniformity when one wants to compare multiple targets at the same time. Therefore we developed TargetDB, a tool that aggregates public information available on given target(s) (Links to disease, safety, 3D structures, ligandability, novelty,…) and assembles it in an easy to read output ready for the researcher to analyze. In this manuscript, we will present the methodology used to develop TargetDB as well as test cases.},
 bibtype = {article},
 author = {De Cesco, Stephane P and Davis, John B and Brennan, Paul E},
 doi = {10.1101/2020.04.21.052878},
 journal = {bioRxiv}
}

When trying to identify new potential therapeutic targets, access to data and knowledge is increasingly important. In a field where new resources and data sources become available every day, it is crucial to be able to take a step back and look at the wider picture in order to identify potential drug targets. While this task is routinely performed by bespoke researchers, it is often time-consuming and lacks uniformity when one wants to compare multiple targets at the same time. Therefore we developed TargetDB, a tool that aggregates public information available on given target(s) (Links to disease, safety, 3D structures, ligandability, novelty,…) and assembles it in an easy to read output ready for the researcher to analyze. In this manuscript, we will present the methodology used to develop TargetDB as well as test cases.

@article{
 title = {TargetDB: A target information aggregation tool and tractability predictor},
 type = {article},
 year = {2020},
 pages = {e0232644},
 volume = {15},
 websites = {https://dx.plos.org/10.1371/journal.pone.0232644},
 month = {9},
 publisher = {Public Library of Science},
 day = {2},
 id = {b7e8fcbb-fd11-3e46-88cc-ed8b46f8ecbc},
 created = {2020-10-09T12:46:40.582Z},
 accessed = {2020-10-09},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2024-04-10T13:32:03.202Z},
 read = {true},
 starred = {true},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 citation_key = {DeCesco2020},
 private_publication = {false},
 abstract = {When trying to identify new potential therapeutic protein targets, access to data and knowledge is increasingly important. In a field where new resources and data sources become available every day, it is crucial to be able to take a step back and look at the wider picture in order to identify potential drug targets. While this task is routinely performed by bespoke literature searches, it is often time-consuming and lacks uniformity when comparing multiple targets at one time. To address this challenge, we developed TargetDB, a tool that aggregates public information available on given target(s) (links to disease, safety, 3D structures, ligandability, novelty, etc.) and assembles it in an easy to read output ready for the researcher to analyze. In addition, we developed a target scoring system based on the desirable attributes of good therapeutic targets and machine learning classification system to categorize novel targets as having promising or challenging tractrability. In this manuscript, we present the methodology used to develop TargetDB as well as test cases.},
 bibtype = {article},
 author = {De Cesco, Stephane and Davis, John B. and Brennan, Paul E.},
 editor = {Barchi, Joseph J},
 doi = {10.1371/journal.pone.0232644},
 journal = {PLOS ONE},
 number = {9}
}

When trying to identify new potential therapeutic protein targets, access to data and knowledge is increasingly important. In a field where new resources and data sources become available every day, it is crucial to be able to take a step back and look at the wider picture in order to identify potential drug targets. While this task is routinely performed by bespoke literature searches, it is often time-consuming and lacks uniformity when comparing multiple targets at one time. To address this challenge, we developed TargetDB, a tool that aggregates public information available on given target(s) (links to disease, safety, 3D structures, ligandability, novelty, etc.) and assembles it in an easy to read output ready for the researcher to analyze. In addition, we developed a target scoring system based on the desirable attributes of good therapeutic targets and machine learning classification system to categorize novel targets as having promising or challenging tractrability. In this manuscript, we present the methodology used to develop TargetDB as well as test cases.

@article{
 title = {Large eQTL meta-analysis reveals differing patterns between cerebral cortical and cerebellar brain regions},
 type = {article},
 year = {2020},
 volume = {7},
 id = {49ae955b-76a8-387d-9543-015925796b62},
 created = {2020-10-21T23:59:00.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2021-04-28T15:28:55.442Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 citation_key = {Sieberts2020a},
 private_publication = {false},
 abstract = {© 2020, The Author(s). The availability of high-quality RNA-sequencing and genotyping data of post-mortem brain collections from consortia such as CommonMind Consortium (CMC) and the Accelerating Medicines Partnership for Alzheimer’s Disease (AMP-AD) Consortium enable the generation of a large-scale brain cis-eQTL meta-analysis. Here we generate cerebral cortical eQTL from 1433 samples available from four cohorts (identifying >4.1 million significant eQTL for >18,000 genes), as well as cerebellar eQTL from 261 samples (identifying 874,836 significant eQTL for >10,000 genes). We find substantially improved power in the meta-analysis over individual cohort analyses, particularly in comparison to the Genotype-Tissue Expression (GTEx) Project eQTL. Additionally, we observed differences in eQTL patterns between cerebral and cerebellar brain regions. We provide these brain eQTL as a resource for use by the research community. As a proof of principle for their utility, we apply a colocalization analysis to identify genes underlying the GWAS association peaks for schizophrenia and identify a potentially novel gene colocalization with lncRNA RP11-677M14.2 (posterior probability of colocalization 0.975).},
 bibtype = {article},
 author = {Sieberts, S.K. and Perumal, T.M. and Carrasquillo, M.M. and Allen, M. and Reddy, J.S. and Hoffman, G.E. and Dang, K.K. and Calley, J. and Ebert, P.J. and Eddy, J. and Wang, X. and Greenwood, A.K. and Mostafavi, S. and Akbarian, S. and Bendl, J. and Breen, M.S. and Brennand, K. and Brown, L. and Browne, A. and Buxbaum, J.D. and Charney, A. and Chess, A. and Couto, L. and Crawford, G. and Devillers, O. and Devlin, B. and Dobbyn, A. and Domenici, E. and Filosi, M. and Flatow, E. and Francoeur, N. and Fullard, J. and Gil, S.E. and Girdhar, K. and Gulyás-Kovács, A. and Gur, R. and Hahn, C.-G. and Haroutunian, V. and Hauberg, M.E. and Huckins, L. and Jacobov, R. and Jiang, Y. and Johnson, J.S. and Kassim, B. and Kim, Y. and Klei, L. and Kramer, R. and Lauria, M. and Lehner, T. and Lewis, D.A. and Lipska, B.K. and Montgomery, K. and Park, R. and Rosenbluh, C. and Roussos, P. and Ruderfer, D.M. and Senthil, G. and Shah, H.R. and Sloofman, L. and Song, L. and Stahl, E. and Sullivan, P. and Visintainer, R. and Wang, J. and Wang, Y.-C. and Wiseman, J. and Xia, E. and Zhang, W. and Zharovsky, E. and Addis, L. and Addo, S.N. and Airey, D.C. and Arnold, M. and Bennett, D.A. and Bi, Y. and Biber, K. and Blach, C. and Bradhsaw, E. and Brennan, P. and Canet-Aviles, R. and Cao, S. and Cavalla, A. and Chae, Y. and Chen, W.W. and Cheng, J. and Collier, D.A. and Dage, J.L. and Dammer, E.B. and Davis, J.W. and Davis, J. and Drake, D. and Duong, D. and Eastwood, B.J. and Ehrlich, M. and Ellingson, B. and Engelmann, B.W. and Esmaeelinieh, S. and Felsky, D. and Funk, C. and Gaiteri, C. and Gandy, S. and Gao, F. and Gileadi, O. and Golde, T. and Grosskurth, S.E. and Gupta, R.R. and Gutteridge, A.X. and Haroutunian, V. and Hooli, B. and Humphryes-Kirilov, N. and Iijima, K. and James, C. and Jung, P.M. and Kaddurah-Daouk, R. and Kastenmuller, G. and Klein, H.-U. and Kummer, M. and Lacor, P.N. and Lah, J. and Laing, E. and Levey, A. and Li, Y. and Lipsky, S. and Liu, Y. and Liu, J. and Liu, Z. and Louie, G. and Lu, T. and Ma, Y. and Matsuoka, Y.Y. and Menon, V. and Miller, B. and Misko, T.P. and Mollon, J.E. and Montgomery, K. and Mukherjee, S. and Noggle, S. and Pao, P.-C. and Pearce, T.Y. and Pearson, N. and Penny, M. and Petyuk, V.A. and Price, N. and Quarless, D.X. and Ravikumar, B. and Ried, J.S. and Ruble, C.L.A. and Runz, H. and Saykin, A.J. and Schadt, E. and Scherschel, J.E. and Seyfried, N. and Shulman, J.M. and Snyder, P. and Soares, H. and Srivastava, G.P. and Stockmann, H. and Taga, M. and Tasaki, S. and Tenenbaum, J. and Tsai, L.-H. and Vasanthakumar, A. and Wachter, A. and Wang, Y. and Wang, H. and Wang, M. and Whelan, C.D. and White, C. and Woo, K.H. and Wren, P. and Wu, J.W. and Xi, H.S. and Yankner, B.A. and Younkin, S.G. and Yu, L. and Zavodszky, M. and Zhang, W. and Zhang, G. and Zhang, B. and Zhu, J. and Omberg, L. and Peters, M.A. and Logsdon, B.A. and De Jager, P.L. and Ertekin-Taner, N. and Mangravite, L.M.},
 doi = {10.1038/s41597-020-00642-8},
 journal = {Scientific Data},
 number = {1}
}

© 2020, The Author(s). The availability of high-quality RNA-sequencing and genotyping data of post-mortem brain collections from consortia such as CommonMind Consortium (CMC) and the Accelerating Medicines Partnership for Alzheimer’s Disease (AMP-AD) Consortium enable the generation of a large-scale brain cis-eQTL meta-analysis. Here we generate cerebral cortical eQTL from 1433 samples available from four cohorts (identifying >4.1 million significant eQTL for >18,000 genes), as well as cerebellar eQTL from 261 samples (identifying 874,836 significant eQTL for >10,000 genes). We find substantially improved power in the meta-analysis over individual cohort analyses, particularly in comparison to the Genotype-Tissue Expression (GTEx) Project eQTL. Additionally, we observed differences in eQTL patterns between cerebral and cerebellar brain regions. We provide these brain eQTL as a resource for use by the research community. As a proof of principle for their utility, we apply a colocalization analysis to identify genes underlying the GWAS association peaks for schizophrenia and identify a potentially novel gene colocalization with lncRNA RP11-677M14.2 (posterior probability of colocalization 0.975).

@article{
 title = {Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in friedreich’s ataxia patient cells},
 type = {article},
 year = {2020},
 pages = {17973-17985},
 volume = {295},
 websites = {http://www.jbc.org/content/early/2020/10/07/jbc.RA120.015533.abstract},
 month = {10},
 day = {7},
 id = {9a7ba817-c7be-3989-b104-cf309fd833f6},
 created = {2020-10-27T08:46:08.725Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2021-04-28T15:28:55.258Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Vilema-Enriquez2020},
 source_type = {JOUR},
 notes = {10.1074/jbc.RA120.015533},
 private_publication = {false},
 abstract = {The molecular mechanisms of reduced frataxin (FXN) expression in Friedreich’s ataxia (FRDA) are linked to epigenetic modification of the FXN locus caused by the disease-associated GAA expansion. Here, we identify that SUV4-20 histone methyltransferases, specifically SUV4-20 H1, play an important role in the regulation of FXN expression and represent a novel therapeutic target. Using a human FXN–GAA–Luciferase repeat expansion genomic DNA reporter model of FRDA, we screened the Structural Genomics Consortium epigenetic probe collection. We found that pharmacological inhibition of the SUV4-20 methyltransferases by the tool compound A-196 increased the expression of FXN by ~1.5-fold in the reporter cell line. In several FRDA cell lines and patient-derived primary peripheral blood mononuclear cells, A-196 increased FXN expression by up to 2-fold, an effect not seen in WT cells. SUV4-20 inhibition was accompanied by a reduction in H4K20me2 and H4K20me3 and an increase in H4K20me1, but only modest (1.4–7.8%) perturbation in genome-wide expression was observed. Finally, based on the structural activity relationship and crystal structure of A-196, novel small molecule A-196 analogs were synthesized and shown to give a 20-fold increase in potency for increasing FXN expression. Overall, our results suggest that histone methylation is important in the regulation of FXN expression and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA.},
 bibtype = {article},
 author = {Vilema-Enríquez, Gabriela and Quinlan, Robert and Kilfeather, Peter and Mazzone, Roberta and Saqlain, Saba and del Molino del Barrio, Irene and Donato, Annalidia and Corda, Gabriele and Li, Fengling and Vedadi, Masoud and Németh, Andrea H. and Brennan, Paul E. and Wade-Martins, Richard},
 doi = {10.1074/jbc.RA120.015533},
 journal = {Journal of Biological Chemistry},
 number = {52}
}

The molecular mechanisms of reduced frataxin (FXN) expression in Friedreich’s ataxia (FRDA) are linked to epigenetic modification of the FXN locus caused by the disease-associated GAA expansion. Here, we identify that SUV4-20 histone methyltransferases, specifically SUV4-20 H1, play an important role in the regulation of FXN expression and represent a novel therapeutic target. Using a human FXN–GAA–Luciferase repeat expansion genomic DNA reporter model of FRDA, we screened the Structural Genomics Consortium epigenetic probe collection. We found that pharmacological inhibition of the SUV4-20 methyltransferases by the tool compound A-196 increased the expression of FXN by ~1.5-fold in the reporter cell line. In several FRDA cell lines and patient-derived primary peripheral blood mononuclear cells, A-196 increased FXN expression by up to 2-fold, an effect not seen in WT cells. SUV4-20 inhibition was accompanied by a reduction in H4K20me2 and H4K20me3 and an increase in H4K20me1, but only modest (1.4–7.8%) perturbation in genome-wide expression was observed. Finally, based on the structural activity relationship and crystal structure of A-196, novel small molecule A-196 analogs were synthesized and shown to give a 20-fold increase in potency for increasing FXN expression. Overall, our results suggest that histone methylation is important in the regulation of FXN expression and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA.

@article{
 title = {Inhibition of histone H3K27 demethylases inactivates brachyury (TBXT) and promotes chordoma cell death},
 type = {article},
 year = {2020},
 volume = {80},
 id = {a2659d1a-04bc-398b-8822-dc436415016d},
 created = {2021-02-04T23:59:00.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2021-04-28T15:28:55.281Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 citation_key = {Cottone2020},
 private_publication = {true},
 abstract = {© American Association for Cancer Research. Expression of the transcription factor brachyury (TBXT) is normally restricted to the embryo, and its silencing is epigenetically regulated. TBXT promotes mesenchymal transition in a subset of common carcinomas, and in chordoma, a rare cancer showing notochordal differentiation, TBXT acts as a putative oncogene. We hypothesized that TBXT expression is controlled through epigenetic inhibition to promote chordoma cell death. Screening of five human chordoma cell lines revealed that pharmacologic inhibition of the histone 3 lysine 27 demethylases KDM6A (UTX) and KDM6B (JMJD3) leads to cell death. This effect was phenocopied by dual genetic inactivation of KDM6A/B using CRISPR/Cas9. Inhibition of KDM6A/B with a novel compound KDOBA67 led to a genome-wide increase in repressive H3K27me3 marks with concomitant reduction in active H3K27ac, H3K9ac, and H3K4me3 marks. TBXT was a KDM6A/B target gene, and chromatin changes at TBXT following KDOBA67 treatment were associated with a reduction in TBXT protein levels in all models tested, including primary patient-derived cultures. In all models tested, KDOBA67 treatment downregulated expression of a network of transcription factors critical for chordoma survival and upregulated pathways dominated by ATF4-driven stress and proapoptotic responses. Blocking the AFT4 stress response did not prevent suppression of TBXT and induction of cell death, but ectopic overexpression of TBXT increased viability, therefore implicating TBXT as a potential therapeutic target of H3K27 demethylase inhibitors in chordoma. Our work highlights how knowledge of normal processes in fetal development can provide insight into tumor-igenesis and identify novel therapeutic approaches.},
 bibtype = {article},
 author = {Cottone, L. and Cribbs, A.P. and Khandelwal, G. and Wells, G. and Ligammari, L. and Philpott, M. and Tumber, A. and Lombard, P. and Hookway, E.S. and Szommer, T. and Johansson, C. and Brennan, P.E. and Pillay, N. and Jenner, R.G. and Oppermann, U. and Flanagan, A.M.},
 doi = {10.1158/0008-5472.CAN-20-1387},
 journal = {Cancer Research},
 number = {20}
}

© American Association for Cancer Research. Expression of the transcription factor brachyury (TBXT) is normally restricted to the embryo, and its silencing is epigenetically regulated. TBXT promotes mesenchymal transition in a subset of common carcinomas, and in chordoma, a rare cancer showing notochordal differentiation, TBXT acts as a putative oncogene. We hypothesized that TBXT expression is controlled through epigenetic inhibition to promote chordoma cell death. Screening of five human chordoma cell lines revealed that pharmacologic inhibition of the histone 3 lysine 27 demethylases KDM6A (UTX) and KDM6B (JMJD3) leads to cell death. This effect was phenocopied by dual genetic inactivation of KDM6A/B using CRISPR/Cas9. Inhibition of KDM6A/B with a novel compound KDOBA67 led to a genome-wide increase in repressive H3K27me3 marks with concomitant reduction in active H3K27ac, H3K9ac, and H3K4me3 marks. TBXT was a KDM6A/B target gene, and chromatin changes at TBXT following KDOBA67 treatment were associated with a reduction in TBXT protein levels in all models tested, including primary patient-derived cultures. In all models tested, KDOBA67 treatment downregulated expression of a network of transcription factors critical for chordoma survival and upregulated pathways dominated by ATF4-driven stress and proapoptotic responses. Blocking the AFT4 stress response did not prevent suppression of TBXT and induction of cell death, but ectopic overexpression of TBXT increased viability, therefore implicating TBXT as a potential therapeutic target of H3K27 demethylase inhibitors in chordoma. Our work highlights how knowledge of normal processes in fetal development can provide insight into tumor-igenesis and identify novel therapeutic approaches.

@article{
 title = {Deliberately Losing Control of C−H Activation Processes in the Design of Small‐Molecule‐Fragment Arrays Targeting Peroxisomal Metabolism},
 type = {article},
 year = {2020},
 pages = {2513-2520},
 volume = {15},
 websites = {https://onlinelibrary.wiley.com/doi/10.1002/cmdc.202000543},
 month = {12},
 publisher = {John Wiley and Sons Ltd},
 day = {15},
 id = {59be5df9-edc6-3d9d-bf46-3db69fec6d9c},
 created = {2021-03-08T08:44:43.850Z},
 accessed = {2021-03-08},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2021-04-28T15:28:55.308Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 citation_key = {KhanTareque2020},
 private_publication = {false},
 abstract = {Combined photochemical arylation, “nuisance effect” (SNAr) reaction sequences have been employed in the design of small arrays for immediate deployment in medium-throughput X-ray protein–ligand structure determination. Reactions were deliberately allowed to run “out of control” in terms of selectivity; for example the ortho-arylation of 2-phenylpyridine gave five products resulting from mono- and bisarylations combined with SNAr processes. As a result, a number of crystallographic hits against NUDT7, a key peroxisomal CoA ester hydrolase, have been identified.},
 bibtype = {article},
 author = {Khan Tareque, Raysa and Hassell‐Hart, Storm and Krojer, Tobias and Bradley, Anthony and Velupillai, Srikannathasan and Talon, Romain and Fairhead, Michael and Day, Iain J. and Bala, Kamlesh and Felix, Robert and Kemmitt, Paul D. and Brennan, Paul and Delft, Frank and Díaz Sáez, Laura and Huber, Kilian and Spencer, John},
 doi = {10.1002/cmdc.202000543},
 journal = {ChemMedChem},
 number = {24}
}

Combined photochemical arylation, “nuisance effect” (SNAr) reaction sequences have been employed in the design of small arrays for immediate deployment in medium-throughput X-ray protein–ligand structure determination. Reactions were deliberately allowed to run “out of control” in terms of selectivity; for example the ortho-arylation of 2-phenylpyridine gave five products resulting from mono- and bisarylations combined with SNAr processes. As a result, a number of crystallographic hits against NUDT7, a key peroxisomal CoA ester hydrolase, have been identified.

@article{
 title = {Design, Synthesis and Characterization of Covalent KDM5 Inhibitors},
 type = {article},
 year = {2019},
 keywords = {KDM5,covalent inhibitors,epigenetics,lysine demethylase},
 pages = {515-519},
 volume = {58},
 websites = {http://doi.wiley.com/10.1002/anie.201810179},
 month = {1},
 publisher = {John Wiley & Sons, Ltd},
 day = {8},
 id = {64513277-4771-3219-bb62-8c3b05234c15},
 created = {2019-01-21T11:42:23.006Z},
 accessed = {2019-01-21},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2024-04-10T13:27:40.490Z},
 read = {true},
 starred = {true},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 citation_key = {Vazquez-Rodriguez2019},
 private_publication = {false},
 bibtype = {article},
 author = {Vazquez-Rodriguez, Saleta and Wright, Miranda and Rogers, Catherine M. and Cribbs, Adam P. and Velupillai, Srikannathasan and Philpott, Martin and Lee, Henry and Dunford, James E. and Huber, Kilian V. M. and Robers, Matthew B. and Vasta, James D. and Thezenas, Marie-Laetitia and Bonham, Sarah and Kessler, Benedikt and Bennett, James and Fedorov, Oleg and Raynaud, Florence and Donovan, Adam and Blagg, Julian and Bavetsias, Vassilios and Oppermann, Udo and Bountra, Chas and Kawamura, Akane and Brennan, Paul E.},
 doi = {10.1002/anie.201810179},
 journal = {Angewandte Chemie International Edition},
 number = {2}
}

@article{
 title = {An Activity-Based Probe Targeting Non-Catalytic, Highly Conserved Amino Acid Residues within Bromodomains},
 type = {article},
 year = {2019},
 keywords = {activity,based protein profiling,bromodomain,chemical proteomics,covalent probes,epigenetics},
 pages = {1007-1012},
 volume = {58},
 websites = {http://doi.wiley.com/10.1002/anie.201807825},
 publisher = {John Wiley & Sons, Ltd},
 id = {5f3b99d3-d8fe-36f4-931e-2a2155b1ba71},
 created = {2019-01-21T11:55:59.457Z},
 accessed = {2019-01-07},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2019-03-21T09:29:21.627Z},
 read = {true},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {DAscenzio2019},
 private_publication = {false},
 bibtype = {article},
 author = {D'Ascenzio, Melissa and Pugh, Kathryn M. and Konietzny, Rebecca and Berridge, Georgina and Tallant, Cynthia and Hashem, Shaima and Monteiro, Octovia and Thomas, Jason R. and Schirle, Markus and Knapp, Stefan and Marsden, Brian and Fedorov, Oleg and Bountra, Chas and Kessler, Benedikt M. and Brennan, Paul E.},
 doi = {10.1002/anie.201807825},
 journal = {Angewandte Chemie International Edition},
 number = {4}
}

@article{
 title = {Chemical Probes},
 type = {article},
 year = {2019},
 pages = {133-152},
 publisher = {Wiley-VCH Verlag GmbH & Co. KGaA Weinheim, Germany},
 id = {8109c281-745c-3fb5-8fc0-fc7742e93541},
 created = {2019-04-25T07:11:43.878Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2019-04-25T07:16:10.350Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {donner2019chemical},
 source_type = {article},
 private_publication = {false},
 bibtype = {article},
 author = {Donner, Amy and King, Heather and Brennan, Paul E and Moustakim, Moses and Zuercher, William J},
 journal = {Epigenetic Drug Discovery}
}

@article{
 title = {Discovery of Pyrrolo[3,2- d]pyrimidin-4-one Derivatives as a New Class of Potent and Cell-Active Inhibitors of P300/CBP-Associated Factor Bromodomain},
 type = {article},
 year = {2019},
 pages = {4526-4542},
 volume = {62},
 websites = {http://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00096},
 month = {4},
 publisher = {American Chemical Society},
 day = {18},
 id = {093bf831-f9bf-3ae2-9e2e-b872f14c569f},
 created = {2019-04-25T07:16:01.164Z},
 accessed = {2019-04-25},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2020-08-18T17:56:43.890Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 citation_key = {Huang2019},
 private_publication = {false},
 abstract = {Herein, we report the discovery of a series of new P300/CBP-associated factor (PCAF) bromodomain (BRD) inhibitors, which were obtained through a hit discovery process and subsequent structure-based optimization and structure-activity relationship analyses toward a retrieved hit compound (12). Among these inhibitors, (R,R)-36n is the most potent one with an IC50 of 7 nM in homogeneous time-resolved fluorescence assay and a KD of 78 nM in isothermal titration calorimetry assay. This compound also exhibited activity against GCN5 and FALZ, but weak or no activity against other 29 BRD proteins and 422 kinases, indicating considerable selectivity. X-ray cocrystal structure analysis revealed the molecular interaction mode and the precise stereochemistry required for bioactivity. Cellular activity, preliminary RNA-seq analysis, and pharmacokinetic properties were also examined for this compound. Collectively, this study provides a versatile tool molecule to explore molecular mechanisms of PCAF BRD regulation and also offers a new lead compound for drug discovery targeting PCAF.},
 bibtype = {article},
 author = {Huang, Lu-Yi and Li, Hui and Li, Lin-Li and Niu, Lu and Seupel, Raina and Wu, Chengyong and Cheng, Wei and Chen, Chong and Ding, Bisen and Brennan, Paul E and Yang, Shengyong},
 doi = {10.1021/acs.jmedchem.9b00096},
 journal = {Journal of Medicinal Chemistry},
 number = {9}
}

Herein, we report the discovery of a series of new P300/CBP-associated factor (PCAF) bromodomain (BRD) inhibitors, which were obtained through a hit discovery process and subsequent structure-based optimization and structure-activity relationship analyses toward a retrieved hit compound (12). Among these inhibitors, (R,R)-36n is the most potent one with an IC50 of 7 nM in homogeneous time-resolved fluorescence assay and a KD of 78 nM in isothermal titration calorimetry assay. This compound also exhibited activity against GCN5 and FALZ, but weak or no activity against other 29 BRD proteins and 422 kinases, indicating considerable selectivity. X-ray cocrystal structure analysis revealed the molecular interaction mode and the precise stereochemistry required for bioactivity. Cellular activity, preliminary RNA-seq analysis, and pharmacokinetic properties were also examined for this compound. Collectively, this study provides a versatile tool molecule to explore molecular mechanisms of PCAF BRD regulation and also offers a new lead compound for drug discovery targeting PCAF.

@article{
 title = {ALK2 inhibitors display beneficial effects in preclinical models of ACVR1 mutant diffuse intrinsic pontine glioma},
 type = {article},
 year = {2019},
 keywords = {CNS cancer,Paediatric cancer,Target validation},
 pages = {156},
 volume = {2},
 websites = {http://www.nature.com/articles/s42003-019-0420-8},
 month = {12},
 publisher = {Nature Publishing Group},
 day = {9},
 id = {fd4dcfc4-3f8a-3f07-b581-c2d5bdce4373},
 created = {2019-05-30T09:02:03.903Z},
 accessed = {2019-05-30},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2019-08-07T17:40:12.680Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 citation_key = {Carvalho2019},
 private_publication = {false},
 abstract = {Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brainstem tumour, with a quarter of patients harbouring somatic mutations in ACVR1, encoding the serine/threonine kinase ALK2. Despite being an amenable drug target, little has been done to-date to systematically evaluate the role of ACVR1 in DIPG, nor to screen currently available inhibitors in patient-derived tumour models. Here we show the dependence of DIPG cells on the mutant receptor, and the preclinical efficacy of two distinct chemotypes of ALK2 inhibitor in vitro and in vivo. We demonstrate the pyrazolo[1,5-a]pyrimidine LDN-193189 and the pyridine LDN-214117 to be orally bioavailable and well-tolerated, with good brain penetration. Treatment of immunodeprived mice bearing orthotopic xenografts of H3.3K27M, ACVR1R206H mutant HSJD-DIPG-007 cells with 25 mg/kg LDN-193189 or LDN-214117 for 28 days extended survival compared with vehicle controls. Development of ALK2 inhibitors with improved potency, selectivity and advantageous pharmacokinetic properties may play an important role in therapy for DIPG patients.},
 bibtype = {article},
 author = {Carvalho, Diana and Taylor, Kathryn R. and Olaciregui, Nagore Gene and Molinari, Valeria and Clarke, Matthew and Mackay, Alan and Ruddle, Ruth and Henley, Alan and Valenti, Melanie and Hayes, Angela and Brandon, Alexis De Haven and Eccles, Suzanne A. and Raynaud, Florence and Boudhar, Aicha and Monje, Michelle and Popov, Sergey and Moore, Andrew S. and Mora, Jaume and Cruz, Ofelia and Vinci, Mara and Brennan, Paul E. and Bullock, Alex N. and Carcaboso, Angel Montero and Jones, Chris},
 doi = {10.1038/s42003-019-0420-8},
 journal = {Communications Biology},
 number = {1}
}

Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brainstem tumour, with a quarter of patients harbouring somatic mutations in ACVR1, encoding the serine/threonine kinase ALK2. Despite being an amenable drug target, little has been done to-date to systematically evaluate the role of ACVR1 in DIPG, nor to screen currently available inhibitors in patient-derived tumour models. Here we show the dependence of DIPG cells on the mutant receptor, and the preclinical efficacy of two distinct chemotypes of ALK2 inhibitor in vitro and in vivo. We demonstrate the pyrazolo[1,5-a]pyrimidine LDN-193189 and the pyridine LDN-214117 to be orally bioavailable and well-tolerated, with good brain penetration. Treatment of immunodeprived mice bearing orthotopic xenografts of H3.3K27M, ACVR1R206H mutant HSJD-DIPG-007 cells with 25 mg/kg LDN-193189 or LDN-214117 for 28 days extended survival compared with vehicle controls. Development of ALK2 inhibitors with improved potency, selectivity and advantageous pharmacokinetic properties may play an important role in therapy for DIPG patients.

@article{
 title = {A chemical toolbox for the study of bromodomains and epigenetic signaling},
 type = {article},
 year = {2019},
 keywords = {Cancer,Cell biology,Chemical biology,Drug discovery},
 pages = {1915},
 volume = {10},
 websites = {http://www.nature.com/articles/s41467-019-09672-2},
 month = {12},
 publisher = {Nature Publishing Group},
 day = {23},
 id = {75a8eb40-2577-3ea7-a93f-f198330c3999},
 created = {2019-05-30T09:03:09.972Z},
 accessed = {2019-05-30},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2019-08-07T17:40:12.490Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 citation_key = {Wu2019},
 private_publication = {false},
 abstract = {Bromodomains (BRDs) are conserved protein interaction modules which recognize (read) acetyl-lysine modifications, however their role(s) in regulating cellular states and their potential as targets for the development of targeted treatment strategies is poorly understood. Here we present a set of 25 chemical probes, selective small molecule inhibitors, covering 29 human bromodomain targets. We comprehensively evaluate the selectivity of this probe-set using BROMOscan and demonstrate the utility of the set identifying roles of BRDs in cellular processes and potential translational applications. For instance, we discovered crosstalk between histone acetylation and the glycolytic pathway resulting in a vulnerability of breast cancer cell lines under conditions of glucose deprivation or GLUT1 inhibition to inhibition of BRPF2/3 BRDs. This chemical probe-set will serve as a resource for future applications in the discovery of new physiological roles of bromodomain proteins in normal and disease states, and as a toolset for bromodomain target validation.},
 bibtype = {article},
 author = {Wu, Qin and Heidenreich, David and Zhou, Stanley and Ackloo, Suzanne and Krämer, Andreas and Nakka, Kiran and Lima-Fernandes, Evelyne and Deblois, Genevieve and Duan, Shili and Vellanki, Ravi N. and Li, Fengling and Vedadi, Masoud and Dilworth, Jeffrey and Lupien, Mathieu and Brennan, Paul E. and Arrowsmith, Cheryl H. and Müller, Susanne and Fedorov, Oleg and Filippakopoulos, Panagis and Knapp, Stefan},
 doi = {10.1038/s41467-019-09672-2},
 journal = {Nature Communications},
 number = {1}
}

Bromodomains (BRDs) are conserved protein interaction modules which recognize (read) acetyl-lysine modifications, however their role(s) in regulating cellular states and their potential as targets for the development of targeted treatment strategies is poorly understood. Here we present a set of 25 chemical probes, selective small molecule inhibitors, covering 29 human bromodomain targets. We comprehensively evaluate the selectivity of this probe-set using BROMOscan and demonstrate the utility of the set identifying roles of BRDs in cellular processes and potential translational applications. For instance, we discovered crosstalk between histone acetylation and the glycolytic pathway resulting in a vulnerability of breast cancer cell lines under conditions of glucose deprivation or GLUT1 inhibition to inhibition of BRPF2/3 BRDs. This chemical probe-set will serve as a resource for future applications in the discovery of new physiological roles of bromodomain proteins in normal and disease states, and as a toolset for bromodomain target validation.

@article{
 title = {Rapid Covalent-Probe Discovery by Electrophile-Fragment Screening},
 type = {article},
 year = {2019},
 pages = {8951-8968},
 volume = {141},
 websites = {http://pubs.acs.org/doi/10.1021/jacs.9b02822},
 month = {6},
 publisher = {American Chemical Society},
 day = {5},
 id = {fa35c245-3b40-354d-9fbe-7e3e0101aa16},
 created = {2019-06-06T08:26:02.146Z},
 accessed = {2019-06-06},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2019-08-07T17:40:12.643Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 citation_key = {Resnick2019},
 private_publication = {false},
 abstract = {Covalent probes can display unmatched potency, selectivity, and duration of action; however, their discovery is challenging. In principle, fragments that can irreversibly bind their target can overcome the low affinity that limits reversible fragment screening, but such electrophilic fragments were considered nonselective and were rarely screened. We hypothesized that mild electrophiles might overcome the selectivity challenge and constructed a library of 993 mildly electrophilic fragments. We characterized this library by a new high-throughput thiol-reactivity assay and screened them against 10 cysteine-containing proteins. Highly reactive and promiscuous fragments were rare and could be easily eliminated. In contrast, we found hits for most targets. Combining our approach with high-throughput crystallography allowed rapid progression to potent and selective probes for two enzymes, the deubiquitinase OTUB2 and the pyrophosphatase NUDT7. No inhibitors were previously known for either. This study highlight...},
 bibtype = {article},
 author = {Resnick, Efrat and Bradley, Anthony and Gan, Jinrui and Douangamath, Alice and Krojer, Tobias and Sethi, Ritika and Geurink, Paul P. and Aimon, Anthony and Amitai, Gabriel and Bellini, Dom and Bennett, James and Fairhead, Michael and Fedorov, Oleg and Gabizon, Ronen and Gan, Jin and Guo, Jingxu and Plotnikov, Alexander and Reznik, Nava and Ruda, Gian Filippo and Díaz-Sáez, Laura and Straub, Verena M. and Szommer, Tamas and Velupillai, Srikannathasan and Zaidman, Daniel and Zhang, Yanling and Coker, Alun R. and Dowson, Christopher G. and Barr, Haim M. and Wang, Chu and Huber, Kilian V.M. and Brennan, Paul E. and Ovaa, Huib and von Delft, Frank and London, Nir},
 doi = {10.1021/jacs.9b02822},
 journal = {Journal of the American Chemical Society},
 number = {22}
}

Covalent probes can display unmatched potency, selectivity, and duration of action; however, their discovery is challenging. In principle, fragments that can irreversibly bind their target can overcome the low affinity that limits reversible fragment screening, but such electrophilic fragments were considered nonselective and were rarely screened. We hypothesized that mild electrophiles might overcome the selectivity challenge and constructed a library of 993 mildly electrophilic fragments. We characterized this library by a new high-throughput thiol-reactivity assay and screened them against 10 cysteine-containing proteins. Highly reactive and promiscuous fragments were rare and could be easily eliminated. In contrast, we found hits for most targets. Combining our approach with high-throughput crystallography allowed rapid progression to potent and selective probes for two enzymes, the deubiquitinase OTUB2 and the pyrophosphatase NUDT7. No inhibitors were previously known for either. This study highlight...

@article{
 title = {A Chemical Probe for Tudor Domain Protein Spindlin1 to Investigate Chromatin Function},
 type = {article},
 year = {2019},
 pages = {9008-9025},
 volume = {62},
 websites = {https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00562},
 month = {10},
 publisher = {American Chemical Society},
 day = {24},
 id = {2b555f75-0963-3562-a9ba-557d46eac579},
 created = {2020-01-26T16:09:51.401Z},
 accessed = {2020-01-26},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2020-01-27T08:15:08.867Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 abstract = {Modifications of histone tails, including lysine/arginine methylation, provide the basis of a “chromatin or histone code”. Proteins that contain “reader” domains can bind to these modifications and form specific effector complexes, which ultimately mediate chromatin function. The spindlin1 (SPIN1) protein contains three Tudor methyllysine/arginine reader domains and was identified as a putative oncogene and transcriptional coactivator. Here we report a SPIN1 chemical probe inhibitor with low nanomolar in vitro activity, exquisite selectivity on a panel of methyl reader and writer proteins, and with submicromolar cellular activity. X-ray crystallography showed that this Tudor domain chemical probe simultaneously engages Tudor domains 1 and 2 via a bidentate binding mode. Small molecule inhibition and siRNA knockdown of SPIN1, as well as chemoproteomic studies, identified genes which are transcriptionally regulated by SPIN1 in squamous cell carcinoma and suggest that SPIN1 may have a role in cancer related ...},
 bibtype = {article},
 author = {Fagan, Vincent and Johansson, Catrine and Gileadi, Carina and Monteiro, Octovia and Dunford, James E. and Nibhani, Reshma and Philpott, Martin and Malzahn, Jessica and Wells, Graham and Faram, Ruth and Cribbs, Adam P. and Halidi, Nadia and Li, Fengling and Chau, Irene and Greschik, Holger and Velupillai, Srikannathasan and Allali-Hassani, Abdellah and Bennett, James and Christott, Thomas and Giroud, Charline and Lewis, Andrew M. and Huber, Kilian V. M. and Athanasou, Nick and Bountra, Chas and Jung, Manfred and Schüle, Roland and Vedadi, Masoud and Arrowsmith, Cheryl and Xiong, Yan and Jin, Jian and Fedorov, Oleg and Farnie, Gillian and Brennan, Paul E. and Oppermann, Udo},
 doi = {10.1021/acs.jmedchem.9b00562},
 journal = {Journal of Medicinal Chemistry},
 number = {20}
}

Modifications of histone tails, including lysine/arginine methylation, provide the basis of a “chromatin or histone code”. Proteins that contain “reader” domains can bind to these modifications and form specific effector complexes, which ultimately mediate chromatin function. The spindlin1 (SPIN1) protein contains three Tudor methyllysine/arginine reader domains and was identified as a putative oncogene and transcriptional coactivator. Here we report a SPIN1 chemical probe inhibitor with low nanomolar in vitro activity, exquisite selectivity on a panel of methyl reader and writer proteins, and with submicromolar cellular activity. X-ray crystallography showed that this Tudor domain chemical probe simultaneously engages Tudor domains 1 and 2 via a bidentate binding mode. Small molecule inhibition and siRNA knockdown of SPIN1, as well as chemoproteomic studies, identified genes which are transcriptionally regulated by SPIN1 in squamous cell carcinoma and suggest that SPIN1 may have a role in cancer related ...

@article{
 title = {A genetics-led approach defines the drug target landscape of 30 immune-related traits},
 type = {article},
 year = {2019},
 pages = {1082-1091},
 volume = {51},
 month = {6},
 publisher = {Springer Nature},
 id = {7e803017-e695-39bc-bf4b-8d0868d63d39},
 created = {2020-01-26T16:10:50.691Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2020-01-26T16:10:50.691Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {fang2019atraits},
 source_type = {article},
 notes = {This is an author version of the article. The final version is available online from the publisher’s website.},
 private_publication = {false},
 abstract = { Most candidate drugs currently fail later-stage clinical trials, largely due to poor prediction of efficacy on early target selection1. Drug targets with genetic support are more likely to be therapeutically valid2,3, but the translational use of genome-scale data such as from genome-wide association studies for drug target discovery in complex diseases remains challenging4,5,6. Here, we show that integration of functional genomic and immune-related annotations, together with knowledge of network connectivity, maximizes the informativeness of genetics for target validation, defining the target prioritization landscape for 30 immune traits at the gene and pathway level. We demonstrate how our genetics-led drug target prioritization approach (the priority index) successfully identifies current therapeutics, predicts activity in high-throughput cellular screens (including L1000, CRISPR, mutagenesis and patient-derived cell assays), enables prioritization of under-explored targets and allows for determination of target-level trait relationships. The priority index is an open-access, scalable system accelerating early-stage drug target selection for immune-mediated disease. },
 bibtype = {article},
 author = {Fang, H and De Wolf, H and Knezevic, B and Burnham, K and Osgood, J and Sekine, T and Berg, L and Göhlmann, H W and Sanniti, A and Lledó Lara, A and Kasela, S and Wegner, J K and O’Callaghan, C A and Bountra, C and Bowness, P and Milani, L and Sundström, Y and Sundström, M and Knight, J and De Cesco, S and Handunnetthi, L and McCann, F E and Chen, L and Brennan, P E and Peeters, P J},
 doi = {10.1038/s41588-019-0456-1},
 journal = {Nature Genetics}
}

Most candidate drugs currently fail later-stage clinical trials, largely due to poor prediction of efficacy on early target selection1. Drug targets with genetic support are more likely to be therapeutically valid2,3, but the translational use of genome-scale data such as from genome-wide association studies for drug target discovery in complex diseases remains challenging4,5,6. Here, we show that integration of functional genomic and immune-related annotations, together with knowledge of network connectivity, maximizes the informativeness of genetics for target validation, defining the target prioritization landscape for 30 immune traits at the gene and pathway level. We demonstrate how our genetics-led drug target prioritization approach (the priority index) successfully identifies current therapeutics, predicts activity in high-throughput cellular screens (including L1000, CRISPR, mutagenesis and patient-derived cell assays), enables prioritization of under-explored targets and allows for determination of target-level trait relationships. The priority index is an open-access, scalable system accelerating early-stage drug target selection for immune-mediated disease.

@article{
 title = {Discovery of a Potent and Selective Fragment-like Inhibitor of Methyllysine Reader Protein Spindlin 1 (SPIN1)},
 type = {article},
 year = {2019},
 pages = {8996-9007},
 volume = {62},
 month = {7},
 publisher = {American Chemical Society},
 id = {186bd545-642b-31a2-bac5-0741f28ab736},
 created = {2020-01-26T16:10:50.703Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2021-12-15T11:49:36.208Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {xiong2019discoveryspin1},
 source_type = {article},
 private_publication = {false},
 abstract = {By screening an epigenetic compound library, we identified that UNC0638, a highly potent inhibitor of the histone methyltransferases G9a and GLP, was a weak inhibitor of SPIN1 (spindlin 1), a methyllysine reader protein. Our optimization of this weak hit resulted in the discovery of a potent, selective, and cell-active SPIN1 inhibitor, compound 3 (MS31). Compound 3 potently inhibited binding of trimethyllysine-containing peptides to SPIN1, displayed high binding affinity, was highly selective for SPIN1 over other epigenetic readers and writers, directly engaged SPIN1 in cells, and was not toxic to nontumorigenic cells. The crystal structure of the SPIN1-compound 3 complex indicated that it selectively binds tudor domain II of SPIN1. We also designed a structurally similar but inactive compound 4 (MS31N) as a negative control. Our results have demonstrated for the first time that potent, selective, and cell-active fragment-like inhibitors can be generated by targeting a single tudor domain.},
 bibtype = {article},
 author = {Xiong, Yan and Greschik, Holger and Johansson, Catrine and Seifert, Ludwig and Bacher, Johannes and Park, Kwang Su and Babault, Nicolas and Martini, Michael and Fagan, Vincent and Li, Fengling and Chau, Irene and Christott, Thomas and Dilworth, David and Barsyte-Lovejoy, Dalia and Vedadi, Masoud and Arrowsmith, Cheryl H. and Brennan, Paul and Fedorov, Oleg and Jung, Manfred and Farnie, Gillian and Liu, Jing and Oppermann, Udo and Schüle, Roland and Jin, Jian},
 doi = {10.1021/acs.jmedchem.9b00522},
 journal = {Journal of Medicinal Chemistry},
 number = {20}
}

By screening an epigenetic compound library, we identified that UNC0638, a highly potent inhibitor of the histone methyltransferases G9a and GLP, was a weak inhibitor of SPIN1 (spindlin 1), a methyllysine reader protein. Our optimization of this weak hit resulted in the discovery of a potent, selective, and cell-active SPIN1 inhibitor, compound 3 (MS31). Compound 3 potently inhibited binding of trimethyllysine-containing peptides to SPIN1, displayed high binding affinity, was highly selective for SPIN1 over other epigenetic readers and writers, directly engaged SPIN1 in cells, and was not toxic to nontumorigenic cells. The crystal structure of the SPIN1-compound 3 complex indicated that it selectively binds tudor domain II of SPIN1. We also designed a structurally similar but inactive compound 4 (MS31N) as a negative control. Our results have demonstrated for the first time that potent, selective, and cell-active fragment-like inhibitors can be generated by targeting a single tudor domain.

@article{
 title = {Synthesis and biological investigation of (+)-JD1, an organometallic BET bromodomain inhibitor},
 type = {article},
 year = {2019},
 month = {12},
 publisher = {American Chemical Society},
 id = {4e441339-de60-3755-a52e-8f72a5f0ac6a},
 created = {2020-01-26T16:10:50.720Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2020-01-26T16:10:50.720Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {hassellhart2019synthesisinhibitor},
 source_type = {article},
 notes = {© 2019 American Chemical Society.},
 private_publication = {false},
 abstract = {(+)-JD1, a rationally designed ferrocene analogue of the BET bromodomain (BRD) probe molecule (+)-JQ1, has been synthesized and evaluated in biophysical, cell-based assays as well as in pharmacokinetic studies. It displays nanomolar activity against BRD isoforms, and its cocrystal structure was determined in complex with the first bromodomain of BRD4 and compared with that of (+)-JQ1, a known BRD4 small-molecule probe. At 1 μM concentration, (+)-JD1 was able to inhibit c-Myc, a key driver in cancer and an indirect target of BRD4.},
 bibtype = {article},
 author = {Hassell-Hart, S and Runcie, A and Krojer, T and Doyle, J and Lineham, E and Ocasio, C A and Neto, B A D and Fedorov, O and Marsh, G and Maple, H and Felix, R and Ciulli, A and Banks, R and Picaud, S and Filippakopoulos, P and von Delft, F and Brennan, P and Stewart, H J S and Chevassut, T J and Walker, M and Austin, C and Morley, S and Spencer, J},
 doi = {10.1021/acs.organomet.9b00750},
 journal = {Organometallics}
}

(+)-JD1, a rationally designed ferrocene analogue of the BET bromodomain (BRD) probe molecule (+)-JQ1, has been synthesized and evaluated in biophysical, cell-based assays as well as in pharmacokinetic studies. It displays nanomolar activity against BRD isoforms, and its cocrystal structure was determined in complex with the first bromodomain of BRD4 and compared with that of (+)-JQ1, a known BRD4 small-molecule probe. At 1 μM concentration, (+)-JD1 was able to inhibit c-Myc, a key driver in cancer and an indirect target of BRD4.

@article{
 title = {C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-ones: Studies towards the identification of potent, cell penetrant Jumonji C domain containing histone lysine demethylase 4 subfamily (KDM4) inhibitors, compound profiling in cell-based target engagement assays},
 type = {article},
 year = {2019},
 pages = {316-337},
 volume = {177},
 month = {5},
 publisher = {Elsevier},
 id = {4ada3c6f-f45f-3165-8527-fbf97355d3ea},
 created = {2020-01-26T16:10:50.921Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2020-01-27T08:15:08.905Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {bavetsias2019c8substitutedassays},
 source_type = {article},
 notes = {© 2019 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).},
 private_publication = {false},
 abstract = {Residues in the histone substrate binding sites that differ between the KDM4 and KDM5 subfamilies were identified. Subsequently, a C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one series was designed to rationally exploit these residue differences between the histone substrate binding sites in order to improve affinity for the KDM4-subfamily over KDM5-subfamily enzymes. In particular, residues E169 and V313 (KDM4A numbering) were targeted. Additionally, conformational restriction of the flexible pyridopyrimidinone C8-substituent was investigated. These approaches yielded potent and cell-penetrant dual KDM4/5-subfamily inhibitors including 19a (KDM4A and KDM5B Ki = 0.004 and 0.007 μM, respectively). Compound cellular profiling in two orthogonal target engagement assays revealed a significant reduction from biochemical to cell-based activity across multiple analogues; this decrease was shown to be consistent with 2OG competition, and suggests that sub-nanomolar biochemical potency will be required with C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one compounds to achieve sub-micromolar target inhibition in cells.},
 bibtype = {article},
 author = {Bavetsias, V and Raynaud, F I and Fedorov, O and Le Bihan, Y-V and Lanigan, R M and Atrash, B and Velupillai, S and Malcolm, A G and England, K S and Ruda, G and Mok, N Y and Tumber, A and Tomlin, K and Saville, H and Shehu, E and McAndrew, C and Carmichael, L and Bennett, J M and Jeganathan, F and Eve, P and Donovan, A and Hayes, A and Wood, F},
 doi = {10.1016/j.ejmech.2019.05.041},
 journal = {European Journal of Medicinal Chemistry}
}

Residues in the histone substrate binding sites that differ between the KDM4 and KDM5 subfamilies were identified. Subsequently, a C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one series was designed to rationally exploit these residue differences between the histone substrate binding sites in order to improve affinity for the KDM4-subfamily over KDM5-subfamily enzymes. In particular, residues E169 and V313 (KDM4A numbering) were targeted. Additionally, conformational restriction of the flexible pyridopyrimidinone C8-substituent was investigated. These approaches yielded potent and cell-penetrant dual KDM4/5-subfamily inhibitors including 19a (KDM4A and KDM5B Ki = 0.004 and 0.007 μM, respectively). Compound cellular profiling in two orthogonal target engagement assays revealed a significant reduction from biochemical to cell-based activity across multiple analogues; this decrease was shown to be consistent with 2OG competition, and suggests that sub-nanomolar biochemical potency will be required with C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one compounds to achieve sub-micromolar target inhibition in cells.

@article{
 title = {Structural Insights into Interaction Mechanisms of Alternative Piperazine-urea YEATS Domain Binders in MLLT1},
 type = {article},
 year = {2019},
 keywords = {MLLT1,YEATS domains,cancer,inhibitor development,piperazine-urea},
 volume = {10},
 id = {28f185f1-d0b9-311c-b5d2-5700a7cd12aa},
 created = {2019-12-19T23:59:00.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2021-02-27T01:23:11.400Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {true},
 abstract = {Copyright © 2019 American Chemical Society. YEATS-domain-containing MLLT1 is an acetyl/acyl-lysine reader domain, which is structurally distinct from well-studied bromodomains and has been strongly associated in development of cancer. Here, we characterized piperazine-urea derivatives as an acetyl/acyl-lysine mimetic moiety for MLLT1. Crystal structures revealed distinct interaction mechanisms of this chemotype compared to the recently described benzimidazole-amide based inhibitors, exploiting different binding pockets within the protein. Thus, the piperazine-urea scaffold offers an alternative strategy for targeting the YEATS domain family.},
 bibtype = {article},
 author = {Ni, X. and Heidenreich, D. and Christott, T. and Bennett, J. and Moustakim, M. and Brennan, P.E. and Fedorov, O. and Knapp, S. and Chaikuad, A.},
 doi = {10.1021/acsmedchemlett.9b00460},
 journal = {ACS Medicinal Chemistry Letters},
 number = {12}
}

Copyright © 2019 American Chemical Society. YEATS-domain-containing MLLT1 is an acetyl/acyl-lysine reader domain, which is structurally distinct from well-studied bromodomains and has been strongly associated in development of cancer. Here, we characterized piperazine-urea derivatives as an acetyl/acyl-lysine mimetic moiety for MLLT1. Crystal structures revealed distinct interaction mechanisms of this chemotype compared to the recently described benzimidazole-amide based inhibitors, exploiting different binding pockets within the protein. Thus, the piperazine-urea scaffold offers an alternative strategy for targeting the YEATS domain family.

@article{
 title = {Identifying Small-Molecule Binding Sites for Epigenetic Proteins at Domain-Domain Interfaces},
 type = {article},
 year = {2018},
 keywords = {Bromodomains,Epigenetics,Histones,Tudor domains,X-ray fragment screening},
 pages = {1051-1057},
 volume = {13},
 id = {1b30f652-3501-3c54-be2a-87e99466d707},
 created = {2018-01-04T16:32:44.878Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:46.431Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Bowkett2018},
 private_publication = {false},
 abstract = {Epigenetics is of rapidly growing field in drug discovery. Of particular interest is the role of post-translational modifications to histone and the proteins that read, write, and erase such modifications. The development of inhibitors for reader domains has focused on single domains. One of the major difficulties of designing inhibitors for reader domains, is that with the notable exception of bromodomains, they tend not to possess a well enclosed binding site amenable to small molecule inhibition. As many of the proteins in epigenetic regulation have multiple domains there are opportunities for designing inhibitors that bind at a domain-domain interface which provide a more suitable interaction pocket. Examination of X-ray structures of multiple domains involved in recognizing and modifying post-translational histone marks using the SiteMap algorithm identified potential binding sites at domain-domain interfaces. For the tandem plant homeodomain-bromodomain of SP100C, a potential inter-domain site identified computationally was validated experimentally by the discovery of ligands by X-ray crystallographic fragment screening.},
 bibtype = {article},
 author = {Bowkett, David and Talon, Romain and Tallant, Cynthia and Schofield, Chris and vonDelft, Frank and Knapp, Stefan and Bruton, Gordon and Brennan, Paul E.},
 doi = {10.1002/cmdc.201800030},
 journal = {ChemMedChem},
 number = {10}
}

Epigenetics is of rapidly growing field in drug discovery. Of particular interest is the role of post-translational modifications to histone and the proteins that read, write, and erase such modifications. The development of inhibitors for reader domains has focused on single domains. One of the major difficulties of designing inhibitors for reader domains, is that with the notable exception of bromodomains, they tend not to possess a well enclosed binding site amenable to small molecule inhibition. As many of the proteins in epigenetic regulation have multiple domains there are opportunities for designing inhibitors that bind at a domain-domain interface which provide a more suitable interaction pocket. Examination of X-ray structures of multiple domains involved in recognizing and modifying post-translational histone marks using the SiteMap algorithm identified potential binding sites at domain-domain interfaces. For the tandem plant homeodomain-bromodomain of SP100C, a potential inter-domain site identified computationally was validated experimentally by the discovery of ligands by X-ray crystallographic fragment screening.

@article{
 title = {Discovery of a novel allosteric inhibitor scaffold for polyadenosine-diphosphate-ribose polymerase 14 (PARP14) macrodomain 2},
 type = {article},
 year = {2018},
 keywords = {Inhibitor Design,Macrodomain,PARP,Poly-ADP ribsose},
 pages = {2965-2972},
 volume = {26},
 id = {d3b8ef3f-7ab1-3616-920a-3fe10fd470e3},
 created = {2018-04-01T07:35:18.913Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:45.934Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Moustakim2018},
 private_publication = {false},
 abstract = {The polyadenosine-diphosphate-ribose polymerase 14 (PARP14) has been implicated in DNA damage response pathways for homologous recombination. PARP14 contains three (ADP ribose binding) macrodomains (MD) whose exact contribution to overall PARP14 function in pathology remains unclear. A medium throughput screen led to the identification of N-(2(-9H-carbazol-1-yl)phenyl)acetamide (GeA-69, 1) as a novel allosteric PARP14 MD2 (second MD of PARP14) inhibitor. We herein report medicinal chemistry around this novel chemotype to afford a sub-micromolar PARP14 MD2 inhibitor. This chemical series provides a novel starting point for further development of PARP14 chemical probes.},
 bibtype = {article},
 author = {Moustakim, Moses and Riedel, Kerstin and Schuller, Marion and Gehring, Andrè P. and Monteiro, Octovia P. and Martin, Sarah P. and Fedorov, Oleg and Heer, Jag and Dixon, Darren J. and Elkins, Jonathan M. and Knapp, Stefan and Bracher, Franz and Brennan, Paul E.},
 doi = {10.1016/j.bmc.2018.03.020},
 journal = {Bioorganic and Medicinal Chemistry},
 number = {11}
}

The polyadenosine-diphosphate-ribose polymerase 14 (PARP14) has been implicated in DNA damage response pathways for homologous recombination. PARP14 contains three (ADP ribose binding) macrodomains (MD) whose exact contribution to overall PARP14 function in pathology remains unclear. A medium throughput screen led to the identification of N-(2(-9H-carbazol-1-yl)phenyl)acetamide (GeA-69, 1) as a novel allosteric PARP14 MD2 (second MD of PARP14) inhibitor. We herein report medicinal chemistry around this novel chemotype to afford a sub-micromolar PARP14 MD2 inhibitor. This chemical series provides a novel starting point for further development of PARP14 chemical probes.

@article{
 title = {Mild, calcium catalysed Beckmann rearrangements},
 type = {article},
 year = {2018},
 pages = {654-657},
 volume = {54},
 month = {1},
 city = {Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7FZ, UK. P.brennan@sgc.ox.ac.uk.},
 id = {0dec6b5f-e15f-3981-9654-fb53d6746c78},
 created = {2018-05-02T07:31:55.853Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-06-15T13:37:56.103Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {kiely-collins2018mildrearrangements.},
 source_type = {article},
 medium = {Print},
 private_publication = {false},
 abstract = {<p>A mild calcium catalysed Beckmann rearrangement has been realised, which forgoes the more traditional harsh reactions conditions associated with the transformation.</p>},
 bibtype = {article},
 author = {Kiely-Collins, H. J. and Sechi, I. and Brennan, P. E. and McLaughlin, M. G.},
 doi = {10.1039/c7cc09491d},
 journal = {Chemical Communications},
 number = {6}
}

A mild calcium catalysed Beckmann rearrangement has been realised, which forgoes the more traditional harsh reactions conditions associated with the transformation.

@article{
 title = {Halogen-Aromatic πInteractions Modulate Inhibitor Residence Times},
 type = {article},
 year = {2018},
 keywords = {Drug residence times,Halogen-π interactions,Iodine,Kinases,Proteins},
 pages = {7220-7224},
 volume = {57},
 month = {3},
 city = {University of Oxford, UNITED KINGDOM.},
 id = {c8af04ff-3f9c-3b75-b3d6-c580d34c6014},
 created = {2018-05-02T07:31:55.876Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:49.735Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {heroven2018halogen-aromatictime.},
 source_type = {article},
 medium = {Print-Electronic},
 private_publication = {false},
 abstract = {Prolonged drug residence times may result in longer lasting drug efficacy, improved pharmacodynamic properties and "kinetic selectivity" over off-targets with fast drug dissociation rates. However, few strategies have been elaborated to rationally modulate drug residence time and thereby to integrate this key property into the drug development process. Here, we show that the interaction between a halogen moiety on an inhibitor and an aromatic residue in the target protein can significantly increase inhibitor residence time. By using the interaction of the serine/threonine kinase haspin with 5-iodotubercidin (5-iTU) derivatives as a model for an archetypal active state (type I) kinase-inhibitor binding mode, we demonstrate that inhibitor residence times markedly increase with the size and polarizability of the halogen atom. This key interaction is dependent on the interactions with an aromatic residue in the gatekeeper position and we observe this interaction in other kinases with an aromatic gatekeeper residue. We provide a detailed mechanistic characterization of the halogen-aromatic π interactions in the haspin-inhibitor complexes by means of kinetic, thermodynamic, and structural measurements along with binding energy calculations. Since halogens are frequently used in drugs and aromatic residues are often present in the binding sites of proteins, our results provide a compelling rationale for introducing aromatic-halogen interactions to prolong drug-target residence times.},
 bibtype = {article},
 author = {Heroven, Christina and Georgi, Victoria and Ganotra, Gaurav K. and Brennan, Paul and Wolfreys, Finn and Wade, Rebecca C. and Fernández-Montalván, Amaury E. and Chaikuad, Apirat and Knapp, Stefan},
 doi = {10.1002/anie.201801666},
 journal = {Angewandte Chemie - International Edition},
 number = {24}
}

Prolonged drug residence times may result in longer lasting drug efficacy, improved pharmacodynamic properties and "kinetic selectivity" over off-targets with fast drug dissociation rates. However, few strategies have been elaborated to rationally modulate drug residence time and thereby to integrate this key property into the drug development process. Here, we show that the interaction between a halogen moiety on an inhibitor and an aromatic residue in the target protein can significantly increase inhibitor residence time. By using the interaction of the serine/threonine kinase haspin with 5-iodotubercidin (5-iTU) derivatives as a model for an archetypal active state (type I) kinase-inhibitor binding mode, we demonstrate that inhibitor residence times markedly increase with the size and polarizability of the halogen atom. This key interaction is dependent on the interactions with an aromatic residue in the gatekeeper position and we observe this interaction in other kinases with an aromatic gatekeeper residue. We provide a detailed mechanistic characterization of the halogen-aromatic π interactions in the haspin-inhibitor complexes by means of kinetic, thermodynamic, and structural measurements along with binding energy calculations. Since halogens are frequently used in drugs and aromatic residues are often present in the binding sites of proteins, our results provide a compelling rationale for introducing aromatic-halogen interactions to prolong drug-target residence times.

@article{
 title = {Bench-Stable Transfer Reagent Facilitates the Generation of Trifluoromethyl-sulfonimidamides},
 type = {article},
 year = {2018},
 websites = {https://doi.org/10.1021/acs.joc.8b01244},
 month = {6},
 publisher = {American Chemical Society},
 day = {22},
 id = {a55dacd5-a71c-385d-be1a-3dcb3d0bafd8},
 created = {2018-07-26T15:41:20.817Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:46.312Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Wright2018},
 source_type = {JOUR},
 notes = {doi: 10.1021/acs.joc.8b01244},
 private_publication = {false},
 bibtype = {article},
 author = {Wright, Miranda and Martínez-Lamenca, Carolina and Leenaerts, Joseph E and Brennan, Paul E and Trabanco, Andrés A and Oehlrich, Daniel},
 doi = {10.1021/acs.joc.8b01244},
 journal = {The Journal of Organic Chemistry}
}

@article{
 title = {A structure-based approach towards identification of inhibitory fragments for eleven-nineteen-leukemia protein (ENL)},
 type = {article},
 year = {2018},
 pages = {acs.jmedchem.8b01457},
 volume = {61},
 websites = {http://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01457},
 month = {12},
 publisher = {American Chemical Society},
 day = {13},
 id = {1e5625da-7746-30b2-a701-9947d34c6ff1},
 created = {2019-01-07T10:30:37.327Z},
 accessed = {2019-01-07},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2019-01-21T11:55:59.679Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 citation_key = {Heidenreich2018},
 private_publication = {false},
 abstract = {Lysine acetylation is an epigenetic mark that is principally recognized by bromodomains, and recently structurally diverse YEATS domains also emerged as readers of lysine acetyl/acylations. Here we present a crystallography-based strategy and the discovery of fragments binding to the ENL YEATS domain, a potential drug target. Crystal structures combined with synthetic efforts led to the identification of a submicromolar binder, providing first starting points for the development of chemical probes for this reader domain family.},
 bibtype = {article},
 author = {Heidenreich, David and Moustakim, Moses and Schmidt, Jurema and Merk, Daniel and Brennan, Paul E. and Fedorov, Oleg and Chaikuad, Apirat and Knapp, Stefan},
 doi = {10.1021/acs.jmedchem.8b01457},
 journal = {Journal of Medicinal Chemistry},
 number = {23}
}

Lysine acetylation is an epigenetic mark that is principally recognized by bromodomains, and recently structurally diverse YEATS domains also emerged as readers of lysine acetyl/acylations. Here we present a crystallography-based strategy and the discovery of fragments binding to the ENL YEATS domain, a potential drug target. Crystal structures combined with synthetic efforts led to the identification of a submicromolar binder, providing first starting points for the development of chemical probes for this reader domain family.

@article{
 title = {Discovery of an MLLT1/3 YEATS Domain Chemical Probe},
 type = {article},
 year = {2018},
 keywords = {MLLT1,MLLT3,YEATS,chemical probes,epigenetics},
 pages = {16302-16307},
 volume = {57},
 websites = {http://doi.wiley.com/10.1002/anie.201810617},
 month = {10},
 day = {5},
 id = {d5d7d1bc-916d-31d7-8316-03c5403d1e86},
 created = {2019-01-21T11:55:59.463Z},
 accessed = {2018-10-10},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2024-05-03T15:19:43.084Z},
 read = {true},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Moustakim2018},
 private_publication = {false},
 abstract = {YEATS domain (YD) containing proteins are an emerging class of epigenetic targets in drug discovery. Dysregulation of these modified lysine‐binding proteins has been linked to the onset and progression of cancers. We herein report the discovery and characterisation of the first small‐molecule chemical probe, SGC‐iMLLT, for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). SGC‐iMLLT is a potent and selective inhibitor of MLLT1/3–histone interactions. Excellent selectivity over other human YD proteins (YEATS2/4) and bromodomains was observed. Furthermore, our probe displays cellular target engagement of MLLT1 and MLLT3. The first small‐molecule X‐ray co‐crystal structures with the MLLT1 YD are also reported. This first‐in‐class probe molecule can be used to understand MLLT1/3‐associated biology and the therapeutic potential of small‐molecule YD inhibitors.},
 bibtype = {article},
 author = {Moustakim, Moses and Christott, Thomas and Monteiro, Octovia P. and Bennett, James and Giroud, Charline and Ward, Jennifer and Rogers, Catherine M. and Smith, Paul and Panagakou, Ioanna and Díaz-Sáez, Laura and Felce, Suet Ling and Gamble, Vicki and Gileadi, Carina and Halidi, Nadia and Heidenreich, David and Chaikuad, Apirat and Knapp, Stefan and Huber, Kilian V.M. M. and Farnie, Gillian and Heer, Jag and Manevski, Nenad and Poda, Gennady and Al-awar, Rima and Dixon, Darren J. and Brennan, Paul E. and Fedorov, Oleg},
 doi = {10.1002/anie.201810617},
 journal = {Angewandte Chemie - International Edition},
 number = {50}
}

YEATS domain (YD) containing proteins are an emerging class of epigenetic targets in drug discovery. Dysregulation of these modified lysine‐binding proteins has been linked to the onset and progression of cancers. We herein report the discovery and characterisation of the first small‐molecule chemical probe, SGC‐iMLLT, for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). SGC‐iMLLT is a potent and selective inhibitor of MLLT1/3–histone interactions. Excellent selectivity over other human YD proteins (YEATS2/4) and bromodomains was observed. Furthermore, our probe displays cellular target engagement of MLLT1 and MLLT3. The first small‐molecule X‐ray co‐crystal structures with the MLLT1 YD are also reported. This first‐in‐class probe molecule can be used to understand MLLT1/3‐associated biology and the therapeutic potential of small‐molecule YD inhibitors.

@misc{
 title = {Identifying small molecule binding sites for epigenetic proteins at domain-domain interfaces},
 type = {misc},
 year = {2018},
 source = {bioRxiv},
 keywords = {Bromodomains,Epigenetics,Histones,MBT domains,PHD domains,PWWP domains,SP100C,SiteMap,Tudor domains,X-ray fragment screening},
 id = {ed2e2537-6c77-36b1-8f2c-5735be5f9afe},
 created = {2020-11-03T23:59:00.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2020-11-06T02:42:35.048Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. Epigenetics is of rapidly growing field in drug discovery. Of particular interest is the role of post-translational modifications to histone and the proteins that read, write, and erase such modifications. The development of inhibitors for reader domains has focused on single domains. One of the major difficulties of designing inhibitors for reader domains, is that with the notable exception of bromodomains, they tend not to possess a well enclosed binding site amenable to small molecule inhibition. As many of the proteins in epigenetic regulation have multiple domains there are opportunities for designing inhibitors that bind at a domain-domain interface which provide a more suitable interaction pocket. Examination of X-ray structures of multiple domains involved in recognizing and modifying post-translational histone marks using the SiteMap algorithm identified potential binding sites at domain-domain interfaces. For the tandem plant homeodomain-bromodomain of SP100C, a potential inter-domain site identified computationally was validated experimentally by the discovery of ligands by X-ray crystallographic fragment screening.},
 bibtype = {misc},
 author = {Bowkett, D. and Talon, R. and Tallant, C. and Schofield, C. and von Delft, F. and Knapp, S. and Bruton, G. and Brennan, P.E.},
 doi = {10.1101/283069}
}

The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. Epigenetics is of rapidly growing field in drug discovery. Of particular interest is the role of post-translational modifications to histone and the proteins that read, write, and erase such modifications. The development of inhibitors for reader domains has focused on single domains. One of the major difficulties of designing inhibitors for reader domains, is that with the notable exception of bromodomains, they tend not to possess a well enclosed binding site amenable to small molecule inhibition. As many of the proteins in epigenetic regulation have multiple domains there are opportunities for designing inhibitors that bind at a domain-domain interface which provide a more suitable interaction pocket. Examination of X-ray structures of multiple domains involved in recognizing and modifying post-translational histone marks using the SiteMap algorithm identified potential binding sites at domain-domain interfaces. For the tandem plant homeodomain-bromodomain of SP100C, a potential inter-domain site identified computationally was validated experimentally by the discovery of ligands by X-ray crystallographic fragment screening.

@article{
 title = {Discovery of a PCAF Bromodomain Chemical Probe},
 type = {article},
 year = {2017},
 keywords = {bromodomains,chemical probes,epigenetics,medicinal chemistry,structure-based design},
 pages = {827-831},
 volume = {56},
 websites = {http://doi.wiley.com/10.1002/anie.201610816},
 month = {1},
 day = {16},
 id = {d5a5cb88-55cc-324f-bbb6-8d7a23127fca},
 created = {2017-01-23T19:27:38.000Z},
 accessed = {2017-01-23},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2024-04-10T13:28:05.397Z},
 read = {true},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Moustakim2017},
 private_publication = {false},
 abstract = {The p300/CBP-associated factor (PCAF) and related GCN5 bromodomain-containing lysine acetyl trans- ferases are members of subfamily I of the bromodomain phylogenetic tree. Iterative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazine-based L-45 (dubbed L-Moses) as the first potent, selective, and cell-active PCAF bromodomain (Brd) inhibitor. Synthesis from readily available (1R,2S)-(?)-nor- ephedrine furnished L-45 in enantiopure form. L-45 was shown to disrupt PCAF-Brd histone H3.3 interaction in cells using a nanoBRET assay, and a co-crystal structure of L-45 with the homologous Brd PfGCN5 from Plasmodium falci- parum rationalizes the high selectivity for PCAF and GCN5 bromodomains. Compound L-45 shows no observable cyto- toxicity in peripheral blood mononuclear cells (PBMC), good cell-permeability, and metabolic stability in human and mouse liver microsomes, supporting its potential for in vivo use. Bromodomains},
 bibtype = {article},
 author = {Moustakim, Moses and Clark, Peter G.K. and Trulli, Laura and Fuentes de Arriba, Angel L. and Ehebauer, Matthias T. and Chaikuad, Apirat and Murphy, Emma J. and Mendez-Johnson, Jacqui and Daniels, Danette and Hou, Chun Feng D. and Lin, Yu Hui and Walker, John R. and Hui, Raymond and Yang, Hongbing and Dorrell, Lucy and Rogers, Catherine M. and Monteiro, Octovia P. and Fedorov, Oleg and Huber, Kilian V.M. and Knapp, Stefan and Heer, Jag and Dixon, Darren J. and Brennan, Paul E.},
 doi = {10.1002/anie.201610816},
 journal = {Angewandte Chemie - International Edition},
 number = {3}
}

The p300/CBP-associated factor (PCAF) and related GCN5 bromodomain-containing lysine acetyl trans- ferases are members of subfamily I of the bromodomain phylogenetic tree. Iterative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazine-based L-45 (dubbed L-Moses) as the first potent, selective, and cell-active PCAF bromodomain (Brd) inhibitor. Synthesis from readily available (1R,2S)-(?)-nor- ephedrine furnished L-45 in enantiopure form. L-45 was shown to disrupt PCAF-Brd histone H3.3 interaction in cells using a nanoBRET assay, and a co-crystal structure of L-45 with the homologous Brd PfGCN5 from Plasmodium falci- parum rationalizes the high selectivity for PCAF and GCN5 bromodomains. Compound L-45 shows no observable cyto- toxicity in peripheral blood mononuclear cells (PBMC), good cell-permeability, and metabolic stability in human and mouse liver microsomes, supporting its potential for in vivo use. Bromodomains

@article{
 title = {Assessing histone demethylase inhibitors in cells: Lessons learned},
 type = {article},
 year = {2017},
 keywords = {2-Oxoglutarate oxygenases,Apoptosis,Cell proliferation,Chromatin,Epigenetics,Histone lysine demethylase,Immunofluorescence,Toxicity},
 pages = {9},
 volume = {10},
 websites = {http://epigeneticsandchromatin.biomedcentral.com/articles/10.1186/s13072-017-0116-6},
 month = {12},
 day = {1},
 id = {7a3536a4-e145-3b0f-8bf8-4e640f9d2cf5},
 created = {2017-04-26T14:13:22.688Z},
 accessed = {2017-04-26},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:49.072Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Hatch2017},
 private_publication = {false},
 abstract = {BACKGROUND Histone lysine demethylases (KDMs) are of interest as drug targets due to their regulatory roles in chromatin organization and their tight associations with diseases including cancer and mental disorders. The first KDM inhibitors for KDM1 have entered clinical trials, and efforts are ongoing to develop potent, selective and cell-active 'probe' molecules for this target class. Robust cellular assays to assess the specific engagement of KDM inhibitors in cells as well as their cellular selectivity are a prerequisite for the development of high-quality inhibitors. Here we describe the use of a high-content cellular immunofluorescence assay as a method for demonstrating target engagement in cells. RESULTS A panel of assays for the Jumonji C subfamily of KDMs was developed to encompass all major branches of the JmjC phylogenetic tree. These assays compare compound activity against wild-type KDM proteins to a catalytically inactive version of the KDM, in which residues involved in the active-site iron coordination are mutated to inactivate the enzyme activity. These mutants are critical for assessing the specific effect of KDM inhibitors and for revealing indirect effects on histone methylation status. The reported assays make use of ectopically expressed demethylases, and we demonstrate their use to profile several recently identified classes of KDM inhibitors and their structurally matched inactive controls. The generated data correlate well with assay results assessing endogenous KDM inhibition and confirm the selectivity observed in biochemical assays with isolated enzymes. We find that both cellular permeability and competition with 2-oxoglutarate affect the translation of biochemical activity to cellular inhibition. CONCLUSIONS High-content-based immunofluorescence assays have been established for eight KDM members of the 2-oxoglutarate-dependent oxygenases covering all major branches of the JmjC-KDM phylogenetic tree. The usage of both full-length, wild-type and catalytically inactive mutant ectopically expressed protein, as well as structure-matched inactive control compounds, allowed for detection of nonspecific effects causing changes in histone methylation as a result of compound toxicity. The developed assays offer a histone lysine demethylase family-wide tool for assessing KDM inhibitors for cell activity and on-target efficacy. In addition, the presented data may inform further studies to assess the cell-based activity of histone lysine methylation inhibitors.},
 bibtype = {article},
 author = {Hatch, Stephanie B. and Yapp, Clarence and Montenegro, Raquel C. and Savitsky, Pavel and Gamble, Vicki and Tumber, Anthony and Ruda, Gian Filippo and Bavetsias, Vassilios and Fedorov, Oleg and Atrash, Butrus and Raynaud, Florence and Lanigan, Rachel and Carmichael, Leanne and Tomlin, Kathy and Burke, Rosemary and Westaway, Susan M. and Brown, Jack A. and Prinjha, Rab K. and Martinez, Elisabeth D. and Oppermann, Udo and Schofield, Christopher J. and Bountra, Chas and Kawamura, Akane and Blagg, Julian and Brennan, Paul E. and Rossanese, Olivia and Müller, Susanne},
 doi = {10.1186/s13072-017-0116-6},
 journal = {Epigenetics and Chromatin},
 number = {1}
}

BACKGROUND Histone lysine demethylases (KDMs) are of interest as drug targets due to their regulatory roles in chromatin organization and their tight associations with diseases including cancer and mental disorders. The first KDM inhibitors for KDM1 have entered clinical trials, and efforts are ongoing to develop potent, selective and cell-active 'probe' molecules for this target class. Robust cellular assays to assess the specific engagement of KDM inhibitors in cells as well as their cellular selectivity are a prerequisite for the development of high-quality inhibitors. Here we describe the use of a high-content cellular immunofluorescence assay as a method for demonstrating target engagement in cells. RESULTS A panel of assays for the Jumonji C subfamily of KDMs was developed to encompass all major branches of the JmjC phylogenetic tree. These assays compare compound activity against wild-type KDM proteins to a catalytically inactive version of the KDM, in which residues involved in the active-site iron coordination are mutated to inactivate the enzyme activity. These mutants are critical for assessing the specific effect of KDM inhibitors and for revealing indirect effects on histone methylation status. The reported assays make use of ectopically expressed demethylases, and we demonstrate their use to profile several recently identified classes of KDM inhibitors and their structurally matched inactive controls. The generated data correlate well with assay results assessing endogenous KDM inhibition and confirm the selectivity observed in biochemical assays with isolated enzymes. We find that both cellular permeability and competition with 2-oxoglutarate affect the translation of biochemical activity to cellular inhibition. CONCLUSIONS High-content-based immunofluorescence assays have been established for eight KDM members of the 2-oxoglutarate-dependent oxygenases covering all major branches of the JmjC-KDM phylogenetic tree. The usage of both full-length, wild-type and catalytically inactive mutant ectopically expressed protein, as well as structure-matched inactive control compounds, allowed for detection of nonspecific effects causing changes in histone methylation as a result of compound toxicity. The developed assays offer a histone lysine demethylase family-wide tool for assessing KDM inhibitors for cell activity and on-target efficacy. In addition, the presented data may inform further studies to assess the cell-based activity of histone lysine methylation inhibitors.

@article{
 title = {Structure-Based Design of Highly Selective Inhibitors of the CREB Binding Protein Bromodomain},
 type = {article},
 year = {2017},
 pages = {5349-5363},
 volume = {60},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/28375629},
 month = {5},
 day = {12},
 city = {United States},
 id = {5e37fa09-b80c-350d-93dd-63676c132123},
 created = {2017-06-08T08:32:32.586Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:48.654Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Denny2017},
 source_type = {JOUR},
 private_publication = {false},
 abstract = {Chemical probes are required for preclinical target validation to interrogate novel biological targets and pathways. Selective inhibitors of the CREB binding protein (CREBBP)/EP300 bromodomains are required to facilitate the elucidation of biology associated with these important epigenetic targets. Medicinal chemistry optimization that paid particular attention to physiochemical properties delivered chemical probes with desirable potency, selectivity, and permeability attributes. An important feature of the optimization process was the successful application of rational structure-based drug design to address bromodomain selectivity issues (particularly against the structurally related BRD4 protein).},
 bibtype = {article},
 author = {Denny, R. Aldrin and Flick, Andrew C. and Coe, Jotham and Langille, Jonathan and Basak, Arindrajit and Liu, Shenping and Stock, Ingrid and Sahasrabudhe, Parag and Bonin, Paul and Hay, Duncan A. and Brennan, Paul E. and Pletcher, Mathew and Jones, Lyn H. and Chekler, Eugene L.Piatnitski},
 doi = {10.1021/acs.jmedchem.6b01839},
 journal = {Journal of Medicinal Chemistry},
 number = {13}
}

Chemical probes are required for preclinical target validation to interrogate novel biological targets and pathways. Selective inhibitors of the CREB binding protein (CREBBP)/EP300 bromodomains are required to facilitate the elucidation of biology associated with these important epigenetic targets. Medicinal chemistry optimization that paid particular attention to physiochemical properties delivered chemical probes with desirable potency, selectivity, and permeability attributes. An important feature of the optimization process was the successful application of rational structure-based drug design to address bromodomain selectivity issues (particularly against the structurally related BRD4 protein).

@article{
 title = {Highly selective inhibition of histone demethylases by de novo macrocyclic peptides},
 type = {article},
 year = {2017},
 pages = {14773},
 volume = {8},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/28382930},
 month = {4},
 day = {6},
 city = {England},
 id = {327067fd-d8ec-346b-b5bd-33a1bd3bcb6c},
 created = {2017-06-08T08:32:32.618Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:48.705Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Kawamura2017},
 source_type = {JOUR},
 private_publication = {false},
 abstract = {JmjC histone demethylases (KDMs) are cancer targets due to their links to cell proliferation, but selective inhibition remains a challenge. Here the authors identify potent inhibitors of KDM4A-C—via in vitro selection from a vast library of cyclic peptides—that show selectivity over other KDMs.},
 bibtype = {article},
 author = {Kawamura, Akane and Münzel, Martin and Kojima, Tatsuya and Yapp, Clarence and Bhushan, Bhaskar and Goto, Yuki and Tumber, Anthony and Katoh, Takayuki and King, Oliver N.F. and Passioura, Toby and Walport, Louise J. and Hatch, Stephanie B. and Madden, Sarah and Müller, Susanne and Brennan, Paul E. and Chowdhury, Rasheduzzaman and Hopkinson, Richard J. and Suga, Hiroaki and Schofield, Christopher J.},
 doi = {10.1038/ncomms14773},
 journal = {Nature Communications}
}

JmjC histone demethylases (KDMs) are cancer targets due to their links to cell proliferation, but selective inhibition remains a challenge. Here the authors identify potent inhibitors of KDM4A-C—via in vitro selection from a vast library of cyclic peptides—that show selectivity over other KDMs.

@article{
 title = {Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells},
 type = {article},
 year = {2017},
 keywords = {2-oxoglutarate oxygenases,JARID1B,KDM5B,chromatin,demethylases,epigenetics,histones,lysine demethylation,myeloma,oncology},
 pages = {371-380},
 volume = {24},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/28262558},
 month = {3},
 day = {16},
 city = {United States},
 id = {a99f23cc-d843-3cde-bbcd-81f8f54ad5ec},
 created = {2017-06-08T08:32:32.633Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:46.105Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Tumber2017},
 source_type = {JOUR},
 private_publication = {false},
 abstract = {Methylation of lysine residues on histone tail is a dynamic epigenetic modification that plays a key role in chromatin structure and gene regulation. Members of the KDM5 (also known as JARID1) sub-family are 2-oxoglutarate (2-OG) and Fe2+-dependent oxygenases acting as histone 3 lysine 4 trimethyl (H3K4me3) demethylases, regulating proliferation, stem cell self-renewal, and differentiation. Here we present the characterization of KDOAM-25, an inhibitor of KDM5 enzymes. KDOAM-25 shows biochemical half maximal inhibitory concentration values of <100 nM for KDM5A-D in vitro, high selectivity toward other 2-OG oxygenases sub-families, and no off-target activity on a panel of 55 receptors and enzymes. In human cell assay systems, KDOAM-25 has a half maximal effective concentration of ∼50 μM and good selectivity toward other demethylases. KDM5B is overexpressed in multiple myeloma and negatively correlated with the overall survival. Multiple myeloma MM1S cells treated with KDOAM-25 show increased global H3K4 methylation at transcriptional start sites and impaired proliferation.},
 bibtype = {article},
 author = {Tumber, Anthony and Nuzzi, Andrea and Hookway, Edward S. and Hatch, Stephanie B. and Velupillai, Srikannathasan and Johansson, Catrine and Kawamura, Akane and Savitsky, Pavel and Yapp, Clarence and Szykowska, Aleksandra and Wu, Na and Bountra, Chas and Strain-Damerell, Claire and Burgess-Brown, Nicola A. and Ruda, Gian Filippo and Fedorov, Oleg and Munro, Shonagh and England, Katherine S. and Nowak, Radoslaw P. and Schofield, Christopher J. and La Thangue, Nicholas B. and Pawlyn, Charlotte and Davies, Faith and Morgan, Gareth and Athanasou, Nick and Müller, Susanne and Oppermann, Udo and Brennan, Paul E.},
 doi = {10.1016/j.chembiol.2017.02.006},
 journal = {Cell Chemical Biology},
 number = {3}
}

Methylation of lysine residues on histone tail is a dynamic epigenetic modification that plays a key role in chromatin structure and gene regulation. Members of the KDM5 (also known as JARID1) sub-family are 2-oxoglutarate (2-OG) and Fe2+-dependent oxygenases acting as histone 3 lysine 4 trimethyl (H3K4me3) demethylases, regulating proliferation, stem cell self-renewal, and differentiation. Here we present the characterization of KDOAM-25, an inhibitor of KDM5 enzymes. KDOAM-25 shows biochemical half maximal inhibitory concentration values of <100 nM for KDM5A-D in vitro, high selectivity toward other 2-OG oxygenases sub-families, and no off-target activity on a panel of 55 receptors and enzymes. In human cell assay systems, KDOAM-25 has a half maximal effective concentration of ∼50 μM and good selectivity toward other demethylases. KDM5B is overexpressed in multiple myeloma and negatively correlated with the overall survival. Multiple myeloma MM1S cells treated with KDOAM-25 show increased global H3K4 methylation at transcriptional start sites and impaired proliferation.

@article{
 title = {Design of a biased potent small molecule inhibitor of the bromodomain and PHD finger-containing (brpf) proteins suitable for cellular and in vivo studies},
 type = {article},
 year = {2017},
 pages = {668-680},
 volume = {60},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/28068087},
 month = {1},
 day = {26},
 city = {United States},
 id = {9172088f-bdaa-37c1-95e9-549df31ac36d},
 created = {2017-06-08T08:32:32.671Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:48.644Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Igoe2017b},
 source_type = {JOUR},
 private_publication = {false},
 abstract = {The BRPF (bromodomain and PHD finger-containing) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Evaluation of the BRPF family as a potential drug target is at an early stage although there is an emerging understanding of a role in acute myeloid leukemia (AML). We report the optimization of fragment hit 5b to 13-d as a biased, potent inhibitor of the BRD of the BRPFs with excellent selectivity over nonclass IV BRD proteins. Evaluation of 13-d in a panel of cancer cell lines showed a selective inhibition of proliferation of a subset of AML lines. Pharmacokinetic studies established that 13-d had properties compatible with oral dosing in mouse models of disease (Fpo 49%). We propose that NI-42 (13-d) is a new chemical probe for the BRPFs suitable for cellular and in vivo studies to explore the fundamental biology of these proteins.},
 bibtype = {article},
 author = {Igoe, Niall and Bayle, Elliott D. and Fedorov, Oleg and Tallant, Cynthia and Savitsky, Pavel and Rogers, Catherine and Owen, Dafydd R. and Deb, Gauri and Somervaille, Tim C.P. and Andrews, David M. and Jones, Neil and Cheasty, Anne and Ryder, Hamish and Brennan, Paul E. and Müller, Susanne and Knapp, Stefan and Fish, Paul V.},
 doi = {10.1021/acs.jmedchem.6b01583},
 journal = {Journal of Medicinal Chemistry},
 number = {2}
}

The BRPF (bromodomain and PHD finger-containing) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Evaluation of the BRPF family as a potential drug target is at an early stage although there is an emerging understanding of a role in acute myeloid leukemia (AML). We report the optimization of fragment hit 5b to 13-d as a biased, potent inhibitor of the BRD of the BRPFs with excellent selectivity over nonclass IV BRD proteins. Evaluation of 13-d in a panel of cancer cell lines showed a selective inhibition of proliferation of a subset of AML lines. Pharmacokinetic studies established that 13-d had properties compatible with oral dosing in mouse models of disease (Fpo 49%). We propose that NI-42 (13-d) is a new chemical probe for the BRPFs suitable for cellular and in vivo studies to explore the fundamental biology of these proteins.

@article{
 title = {BRD3 and BRD4 BET Bromodomain Proteins Differentially Regulate Skeletal Myogenesis},
 type = {article},
 year = {2017},
 pages = {6153},
 volume = {7},
 id = {8c36e77f-f742-3feb-ab27-076afd1ec222},
 created = {2017-08-08T17:55:10.354Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:50.339Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Roberts2017},
 private_publication = {false},
 abstract = {© 2017 The Author(s). Myogenic differentiation proceeds through a highly coordinated cascade of gene activation that necessitates epigenomic changes in chromatin structure. Using a screen of small molecule epigenetic probes we identified three compounds which inhibited myogenic differentiation in C2C12 myoblasts; (+)-JQ1, PFI-1, and Bromosporine. These molecules target Bromodomain and Extra Terminal domain (BET) proteins, which are epigenetic readers of acetylated histone lysine tail residues. BETi-mediated anti-myogenic effects were also observed in a model of MYOD1-mediated myogenic conversion of human fibroblasts, and in primary mouse and human myoblasts. All three BET proteins BRD2, BRD3 and BRD4 exhibited distinct and dynamic patterns of protein expression over the course of differentiation without concomitant changes in mRNA levels, suggesting that BET proteins are regulated at the post-transcriptional level. Specific BET protein knockdown by RNA interference revealed that BRD4 was required for myogenic differentiation, whereas BRD3 down-regulation resulted in enhanced myogenic differentiation. ChIP experiments revealed a preferential binding of BRD4 to the Myog promoter during C2C12 myoblast differentiation, co-incident with increased levels of H3K27 acetylation. These results have identified an essential role for BET proteins in the regulation of skeletal myogenesis, and assign distinct functions to BRD3 and BRD4.},
 bibtype = {article},
 author = {Roberts, Thomas C. and Etxaniz, Usue and Dall'agnese, Alessandra and Wu, Shwu Yuan and Chiang, Cheng Ming and Brennan, Paul E. and Wood, Matthew J.A. and Puri, Pier Lorenzo},
 doi = {10.1038/s41598-017-06483-7},
 journal = {Scientific Reports},
 number = {1}
}

© 2017 The Author(s). Myogenic differentiation proceeds through a highly coordinated cascade of gene activation that necessitates epigenomic changes in chromatin structure. Using a screen of small molecule epigenetic probes we identified three compounds which inhibited myogenic differentiation in C2C12 myoblasts; (+)-JQ1, PFI-1, and Bromosporine. These molecules target Bromodomain and Extra Terminal domain (BET) proteins, which are epigenetic readers of acetylated histone lysine tail residues. BETi-mediated anti-myogenic effects were also observed in a model of MYOD1-mediated myogenic conversion of human fibroblasts, and in primary mouse and human myoblasts. All three BET proteins BRD2, BRD3 and BRD4 exhibited distinct and dynamic patterns of protein expression over the course of differentiation without concomitant changes in mRNA levels, suggesting that BET proteins are regulated at the post-transcriptional level. Specific BET protein knockdown by RNA interference revealed that BRD4 was required for myogenic differentiation, whereas BRD3 down-regulation resulted in enhanced myogenic differentiation. ChIP experiments revealed a preferential binding of BRD4 to the Myog promoter during C2C12 myoblast differentiation, co-incident with increased levels of H3K27 acetylation. These results have identified an essential role for BET proteins in the regulation of skeletal myogenesis, and assign distinct functions to BRD3 and BRD4.

@article{
 title = {The SGC beyond structural genomics: redefining the role of 3D structures by coupling genomic stratification with fragment-based discovery},
 type = {article},
 year = {2017},
 keywords = {FBDD,Fragment screening,Genetic hits,SBDD,SGC,Structural Genomics},
 pages = {495-503},
 volume = {61},
 websites = {https://doi.org/10.1042/EBC20170051},
 month = {11},
 publisher = {Portland Press Limited},
 day = {8},
 id = {6dc1d040-9e00-393f-8241-03100f76b1ec},
 created = {2017-12-06T13:16:59.251Z},
 accessed = {2017-12-06},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:49.989Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Bradley2017},
 private_publication = {false},
 abstract = {The ongoing explosion in genomics data has long since outpaced the capacity of conven-tional biochemical methodology to verify the large number of hypotheses that emerge from the analysis of such data. In contrast, it is still a gold-standard for early phenotypic valida-tion towards small-molecule drug discovery to use probe molecules (or tool compounds), notwithstanding the difficulty and cost of generating them. Rational structure-based ap-proaches to ligand discovery have long promised the efficiencies needed to close this divergence; in practice, however, this promise remains largely unfulfilled, for a host of well-rehearsed reasons and despite the huge technical advances spearheaded by the struc-tural genomics initiatives of the noughties. Therefore the current, fourth funding phase of the Structural Genomics Consortium (SGC), building on its extensive experience in struc-tural biology of novel targets and design of protein inhibitors, seeks to redefine what it means to do structural biology for drug discovery. We developed the concept of a Target Enabling Package (TEP) that provides, through reagents, assays and data, the missing link between genetic disease linkage and the development of usefully potent compounds. There are multiple prongs to the ambition: rigorously assessing targets' genetic disease linkages through crowdsourcing to a network of collaborating experts; establishing a systematic ap-proach to generate the protocols and data that comprise each target's TEP; developing new, X-ray-based fragment technologies for generating high quality chemical matter quickly and cheaply; and exploiting a stringently open access model to build multidisciplinary partner-ships throughout academia and industry. By learning how to scale these approaches, the SGC aims to make structures finally serve genomics, as originally intended, and demon-strate how 3D structures systematically allow new modes of druggability to be discovered for whole classes of targets.},
 bibtype = {article},
 author = {Bradley, Anthony R and Echalier, Aude and Fairhead, Michael and Strain-Damerell, Claire and Brennan, Paul and Bullock, Alex N and Burgess-Brown, Nicola A and Carpenter, Elisabeth P and Gileadi, Opher and Marsden, Brian D and Lee, Wen Hwa and Yue, Wyatt and Bountra, Chas and Von Delft, Frank},
 doi = {10.1042/EBC20170051},
 journal = {Essays in Biochemistry},
 number = {5}
}

The ongoing explosion in genomics data has long since outpaced the capacity of conven-tional biochemical methodology to verify the large number of hypotheses that emerge from the analysis of such data. In contrast, it is still a gold-standard for early phenotypic valida-tion towards small-molecule drug discovery to use probe molecules (or tool compounds), notwithstanding the difficulty and cost of generating them. Rational structure-based ap-proaches to ligand discovery have long promised the efficiencies needed to close this divergence; in practice, however, this promise remains largely unfulfilled, for a host of well-rehearsed reasons and despite the huge technical advances spearheaded by the struc-tural genomics initiatives of the noughties. Therefore the current, fourth funding phase of the Structural Genomics Consortium (SGC), building on its extensive experience in struc-tural biology of novel targets and design of protein inhibitors, seeks to redefine what it means to do structural biology for drug discovery. We developed the concept of a Target Enabling Package (TEP) that provides, through reagents, assays and data, the missing link between genetic disease linkage and the development of usefully potent compounds. There are multiple prongs to the ambition: rigorously assessing targets' genetic disease linkages through crowdsourcing to a network of collaborating experts; establishing a systematic ap-proach to generate the protocols and data that comprise each target's TEP; developing new, X-ray-based fragment technologies for generating high quality chemical matter quickly and cheaply; and exploiting a stringently open access model to build multidisciplinary partner-ships throughout academia and industry. By learning how to scale these approaches, the SGC aims to make structures finally serve genomics, as originally intended, and demon-strate how 3D structures systematically allow new modes of druggability to be discovered for whole classes of targets.

@article{
 title = {Discovery of a Highly Selective Cell-Active Inhibitor of the Histone Lysine Demethylases KDM2/7},
 type = {article},
 year = {2017},
 keywords = {asymmetric catalysis,epigenetics,inhibitors,lysine demethylases},
 pages = {15555-15559},
 volume = {56},
 websites = {http://doi.wiley.com/10.1002/anie.201706788},
 month = {12},
 day = {4},
 id = {64f096da-2a2f-3e59-8ed1-d1fb205f32af},
 created = {2017-12-06T13:17:45.034Z},
 accessed = {2017-12-06},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2021-03-22T09:24:59.564Z},
 read = {true},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Gerken2017},
 private_publication = {false},
 abstract = {Histone lysine demethylases (KDMs) are of critical importance in the epigenetic regulation of gene expression, yet there are few selective, cell-permeable inhibitors or suitable tool compounds for these enzymes. We describe the discovery of a new class of inhibitor that is highly potent towards the histone lysine demethylases KDM2A/7A. A modular synthetic approach was used to explore the chemical space and accelerate the investigation of key structure-activity relationships, leading to the development of a small molecule with around 75-fold selectivity towards KDM2A/7A versus other KDMs, as well as cellular activity at low micromolar concentrations.},
 bibtype = {article},
 author = {Gerken, Philip A. and Wolstenhulme, Jamie R. and Tumber, Anthony and Hatch, Stephanie B. and Zhang, Yijia and Müller, Susanne and Chandler, Shane A. and Mair, Barbara and Li, Fengling and Nijman, Sebastian M.B. and Konietzny, Rebecca and Szommer, Tamas and Yapp, Clarence and Fedorov, Oleg and Benesch, Justin L.P. and Vedadi, Masoud and Kessler, Benedikt M. and Kawamura, Akane and Brennan, Paul E. and Smith, Martin D.},
 doi = {10.1002/anie.201706788},
 journal = {Angewandte Chemie - International Edition},
 number = {49}
}

Histone lysine demethylases (KDMs) are of critical importance in the epigenetic regulation of gene expression, yet there are few selective, cell-permeable inhibitors or suitable tool compounds for these enzymes. We describe the discovery of a new class of inhibitor that is highly potent towards the histone lysine demethylases KDM2A/7A. A modular synthetic approach was used to explore the chemical space and accelerate the investigation of key structure-activity relationships, leading to the development of a small molecule with around 75-fold selectivity towards KDM2A/7A versus other KDMs, as well as cellular activity at low micromolar concentrations.

@article{
 title = {Selective Targeting of Bromodomains of the Bromodomain-PHD Fingers Family Impairs Osteoclast Differentiation},
 type = {article},
 year = {2017},
 pages = {2619-2630},
 volume = {12},
 websites = {http://pubs.acs.org/doi/abs/10.1021/acschembio.7b00481},
 month = {10},
 publisher = {American Chemical Society},
 day = {20},
 id = {151e6c75-0847-3f86-8a8c-950e35217fb3},
 created = {2017-12-06T13:19:15.332Z},
 accessed = {2017-12-06},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:50.095Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Meier2017},
 private_publication = {false},
 abstract = {Histone acetyltransferases of the MYST family are recruited to chromatin by BRPF scaffolding proteins. We explored functional consequences and the therapeutic potential of inhibitors targeting acetyl-lysine dependent protein interaction domains (bromodomains) present in BRPF1–3 in bone maintenance. We report three potent and selective inhibitors: one (PFI-4) with high selectivity for the BRPF1B isoform and two pan-BRPF bromodomain inhibitors (OF-1, NI-57). The developed inhibitors displaced BRPF bromodomains from chromatin and did not inhibit cell growth and proliferation. Intriguingly, the inhibitors impaired RANKL-induced differentiation of primary murine bone marrow cells and human primary monocytes into bone resorbing osteoclasts by specifically repressing transcriptional programs required for osteoclastogenesis. The data suggest a key role of BRPF in regulating gene expression during osteoclastogenesis, and the excellent druggability of these bromodomains may lead to new treatment strategies for pati...},
 bibtype = {article},
 author = {Meier, Julia C. and Tallant, Cynthia and Fedorov, Oleg and Witwicka, Hanna and Hwang, Sung Yong and Van Stiphout, Ruud G. and Lambert, Jean Philippe and Rogers, Catherine and Yapp, Clarence and Gerstenberger, Brian S. and Fedele, Vita and Savitsky, Pavel and Heidenreich, David and Daniels, Danette L. and Owen, Dafydd R. and Fish, Paul V. and Igoe, Niall M. and Bayle, Elliott D. and Haendler, Bernard and Oppermann, Udo C.T. and Buffa, Francesca and Brennan, Paul E. and Müller, Susanne and Gingras, Anne Claude and Odgren, Paul R. and Birnbaum, Mark J. and Knapp, Stefan},
 doi = {10.1021/acschembio.7b00481},
 journal = {ACS Chemical Biology},
 number = {10}
}

Histone acetyltransferases of the MYST family are recruited to chromatin by BRPF scaffolding proteins. We explored functional consequences and the therapeutic potential of inhibitors targeting acetyl-lysine dependent protein interaction domains (bromodomains) present in BRPF1–3 in bone maintenance. We report three potent and selective inhibitors: one (PFI-4) with high selectivity for the BRPF1B isoform and two pan-BRPF bromodomain inhibitors (OF-1, NI-57). The developed inhibitors displaced BRPF bromodomains from chromatin and did not inhibit cell growth and proliferation. Intriguingly, the inhibitors impaired RANKL-induced differentiation of primary murine bone marrow cells and human primary monocytes into bone resorbing osteoclasts by specifically repressing transcriptional programs required for osteoclastogenesis. The data suggest a key role of BRPF in regulating gene expression during osteoclastogenesis, and the excellent druggability of these bromodomains may lead to new treatment strategies for pati...

@article{
 title = {Design of a Chemical Probe for the Bromodomain and Plant Homeodomain Finger-Containing (BRPF) Family of Proteins},
 type = {article},
 year = {2017},
 pages = {6998-7011},
 volume = {60},
 websites = {http://pubs.acs.org/doi/10.1021/acs.jmedchem.7b00611},
 month = {8},
 publisher = {American Chemical Society},
 day = {24},
 id = {6bcc13ff-f999-3184-ba58-90b23ddd4cb3},
 created = {2017-12-06T13:19:53.761Z},
 accessed = {2017-12-06},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:50.020Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Igoe2017a},
 private_publication = {false},
 abstract = {The bromodomain and plant homeodomain finger-containing (BRPF) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Here, we describe NI-57 (16) as new pan-BRPF chemical probe of the bromodomain (BRD) of the BRPFs. Inhibitor 16 preferentially bound the BRD of BRPF1 and BRPF2 over BRPF3, whereas binding to BRD9 was weaker. Compound 16 has excellent selectivity over nonclass IV BRD proteins. Target engagement of BRPF1B and BRPF2 with 16 was demonstrated in nanoBRET and FRAP assays. The binding of 16 to BRPF1B was rationalized through an X-ray cocrystal structure determination, which showed a flipped binding orientation when compared to previous structures. We report studies that show 16 has functional activity in cellular assays by modulation of the phenotype at low micromolar concentrations in both cancer and inflammatory models. Pharmacokinetic data for 16 was generated in mouse with single dose administration showing favorable oral b...},
 bibtype = {article},
 author = {Igoe, Niall and Bayle, Elliott D. and Tallant, Cynthia and Fedorov, Oleg and Meier, Julia C. and Savitsky, Pavel and Rogers, Catherine and Morias, Yannick and Scholze, Sarah and Boyd, Helen and Cunoosamy, Danen and Andrews, David M. and Cheasty, Anne and Brennan, Paul E. and Müller, Susanne and Knapp, Stefan and Fish, Paul V.},
 doi = {10.1021/acs.jmedchem.7b00611},
 journal = {Journal of Medicinal Chemistry},
 number = {16}
}

The bromodomain and plant homeodomain finger-containing (BRPF) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Here, we describe NI-57 (16) as new pan-BRPF chemical probe of the bromodomain (BRD) of the BRPFs. Inhibitor 16 preferentially bound the BRD of BRPF1 and BRPF2 over BRPF3, whereas binding to BRD9 was weaker. Compound 16 has excellent selectivity over nonclass IV BRD proteins. Target engagement of BRPF1B and BRPF2 with 16 was demonstrated in nanoBRET and FRAP assays. The binding of 16 to BRPF1B was rationalized through an X-ray cocrystal structure determination, which showed a flipped binding orientation when compared to previous structures. We report studies that show 16 has functional activity in cellular assays by modulation of the phenotype at low micromolar concentrations in both cancer and inflammatory models. Pharmacokinetic data for 16 was generated in mouse with single dose administration showing favorable oral b...

@inproceedings{
 title = {Di-iodotyrosinated peptide imaging of cartilage (DIPIC)},
 type = {inproceedings},
 year = {2017},
 pages = {A7-A7},
 volume = {98},
 issue = {3},
 websites = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000408620000013&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=4fd6f7d59a501f9b8bac2be37914c43e},
 month = {6},
 id = {1e2c8b9d-5ce4-3c48-911f-3ed69b10091b},
 created = {2018-07-09T12:39:48.414Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:46.320Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Fowkes2017},
 source_type = {CONF},
 private_publication = {false},
 bibtype = {inproceedings},
 author = {Fowkes, M M and Borges, P D N and Brennan, P E and Vincent, T L and Lim, N H},
 booktitle = {International Journal of Experimental Pathology}
}

@article{
 title = {Discovery of a Chemical Tool Inhibitor Targeting the Bromodomains of TRIM24 and BRPF},
 type = {article},
 year = {2016},
 pages = {1642-1647},
 volume = {59},
 websites = {http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b00458},
 edition = {2015/05/15},
 id = {8a861d2d-a38c-3b1a-99d8-4a15a13fe2d6},
 created = {2015-10-07T14:20:51.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:50.586Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Bennett2015},
 source_type = {Journal Article},
 language = {Eng},
 notes = {<b>From Duplicate 1 (<i>Discovery of a Chemical Tool Inhibitor Targeting the Bromodomains of TRIM24 and BRPF</i> - Bennett, J; Fedorov, O; Tallant, C; Monteiro, O; Meier, J; Gamble, V; Savitsky, P; Nunez-Alonso, G A; Haendler, B; Rogers, C; Brennan, P E; Muller, S; Knapp, S)<br/></b><br/>1520-4804<br/>Bennett, James<br/>Fedorov, Oleg<br/>Tallant, Cynthia<br/>Monteiro, Octovia<br/>Meier, Julia<br/>Gamble, Vicky<br/>Savitsky, Pavel<br/>Nunez-Alonso, Graciela A<br/>Haendler, Bernard<br/>Rogers, Catherine<br/>Brennan, Paul E<br/>Muller, Susanne<br/>Knapp, Stefan<br/>Journal article<br/>J Med Chem. 2015 May 20.},
 private_publication = {false},
 abstract = {TRIM24 is a transcriptional regulator as well as an E3 ubiquitin ligase. It is overexpressed in diverse tumors, and high expression levels have been linked to poor prognosis in breast cancer patients. TRIM24 contains a PHD/bromodomain offering the opportunity to develop protein interaction inhibitors that target this protein interaction module. Here we identified potent acetyl-lysine mimetic benzimidazolones TRIM24 bromodomain inhibitors. The best compound of this series is a selective BRPF1B/TRIM24 dual inhibitor that bound with a KD of 137 and 222 nM, respectively, but exerted good selectivity over other bromodomains. Cellular activity of the inhibitor was demonstrated using FRAP assays as well as cell viability data.},
 bibtype = {article},
 author = {Bennett, James and Fedorov, Oleg and Tallant, Cynthia and Monteiro, Octovia and Meier, Julia and Gamble, Vicky and Savitsky, Pavel and Nunez-Alonso, Graciela A. and Haendler, Bernard and Rogers, Catherine and Brennan, Paul E. and Müller, Susanne and Knapp, Stefan},
 doi = {10.1021/acs.jmedchem.5b00458},
 journal = {Journal of Medicinal Chemistry},
 number = {4}
}

TRIM24 is a transcriptional regulator as well as an E3 ubiquitin ligase. It is overexpressed in diverse tumors, and high expression levels have been linked to poor prognosis in breast cancer patients. TRIM24 contains a PHD/bromodomain offering the opportunity to develop protein interaction inhibitors that target this protein interaction module. Here we identified potent acetyl-lysine mimetic benzimidazolones TRIM24 bromodomain inhibitors. The best compound of this series is a selective BRPF1B/TRIM24 dual inhibitor that bound with a KD of 137 and 222 nM, respectively, but exerted good selectivity over other bromodomains. Cellular activity of the inhibitor was demonstrated using FRAP assays as well as cell viability data.

@article{
 title = {Structure-Based Identification of Inhibitory Fragments Targeting the p300/CBP-Associated Factor Bromodomain},
 type = {article},
 year = {2016},
 pages = {1648-1653},
 volume = {59},
 websites = {http://dx.doi.org/10.1021/acs.jmedchem.5b01719},
 month = {1},
 publisher = {American Chemical Society},
 day = {13},
 id = {aac6d6e5-a4c8-3337-9027-3a464134cfdf},
 created = {2016-01-29T10:49:48.000Z},
 accessed = {2016-01-29},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:49.189Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Chaikuad2016},
 private_publication = {false},
 abstract = {The P300/CBP-associated factor plays a central role in retroviral infection and cancer development, and the C-terminal bromodomain provides an opportunity for selective targeting. Here, we report several new classes of acetyl-lysine mimetic ligands ranging from mM to low micromolar affinity that were identified using fragment screening approaches. The binding modes of the most attractive fragments were determined using high resolution crystal structures providing chemical starting points and structural models for the development of potent and selective PCAF inhibitors.},
 bibtype = {article},
 author = {Chaikuad, Apirat and Lang, Steffen and Brennan, Paul E. and Temperini, Claudia and Fedorov, Oleg and Hollander, Johan and Nachane, Ruta and Abell, Chris and Müller, Susanne and Siegal, Gregg and Knapp, Stefan},
 doi = {10.1021/acs.jmedchem.5b01719},
 journal = {Journal of Medicinal Chemistry},
 number = {4}
}

The P300/CBP-associated factor plays a central role in retroviral infection and cancer development, and the C-terminal bromodomain provides an opportunity for selective targeting. Here, we report several new classes of acetyl-lysine mimetic ligands ranging from mM to low micromolar affinity that were identified using fragment screening approaches. The binding modes of the most attractive fragments were determined using high resolution crystal structures providing chemical starting points and structural models for the development of potent and selective PCAF inhibitors.

@article{
 title = {A poised fragment library enables rapid synthetic expansion yielding the first reported inhibitors of PHIP(2), an atypical bromodomain},
 type = {article},
 year = {2016},
 pages = {2322-2330},
 volume = {7},
 websites = {http://xlink.rsc.org/?DOI=C5SC03115J},
 publisher = {Royal Society of Chemistry},
 id = {7561975c-c867-342f-a40e-65d3f055c4ed},
 created = {2016-02-01T08:09:31.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2024-05-02T14:04:14.785Z},
 read = {true},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Cox2016},
 folder_uuids = {5358531d-d036-484b-937b-88c0f1ef606b},
 private_publication = {false},
 abstract = {<p> High concentration crystal soaking of poised fragments and one-step elaboration identified compound <bold>17</bold> as an inhibitor of the PHIP(2) bromodomain. </p>},
 bibtype = {article},
 author = {Cox, Oakley B. and Krojer, Tobias and Collins, Patrick and Monteiro, Octovia and Talon, Romain and Bradley, Anthony and Fedorov, Oleg and Amin, Jahangir and Marsden, Brian D. and Spencer, John and Von Delft, Frank and Brennan, Paul E.},
 doi = {10.1039/c5sc03115j},
 journal = {Chemical Science},
 number = {3}
}

High concentration crystal soaking of poised fragments and one-step elaboration identified compound 17 as an inhibitor of the PHIP(2) bromodomain.

@article{
 title = {8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors},
 type = {article},
 year = {2016},
 pages = {1388-1409},
 volume = {59},
 websites = {http://dx.doi.org/10.1021/acs.jmedchem.5b01635},
 month = {1},
 publisher = {American Chemical Society},
 day = {7},
 id = {9ab9f57c-a78e-3aa1-bd70-042fd761daf2},
 created = {2016-02-27T12:45:35.000Z},
 accessed = {2016-01-15},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:49.038Z},
 read = {true},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Bavetsias2016},
 folder_uuids = {938fbf5b-84f5-458e-a688-7301b85f5826},
 private_publication = {false},
 abstract = {We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.},
 bibtype = {article},
 author = {Bavetsias, Vassilios and Lanigan, Rachel M. and Ruda, Gian Filippo and Atrash, Butrus and McLaughlin, Mark G. and Tumber, Anthony and Mok, N. Yi and Le Bihan, Yann Vaï and Dempster, Sally and Boxall, Katherine J. and Jeganathan, Fiona and Hatch, Stephanie B. and Savitsky, Pavel and Velupillai, Srikannathasan and Krojer, Tobias and England, Katherine S. and Sejberg, Jimmy and Thai, Ching and Donovan, Adam and Pal, Akos and Scozzafava, Giuseppe and Bennett, James M. and Kawamura, Akane and Johansson, Catrine and Szykowska, Aleksandra and Gileadi, Carina and Burgess-Brown, Nicola A. and Von Delft, Frank and Oppermann, Udo and Walters, Zoe and Shipley, Janet and Raynaud, Florence I. and Westaway, Susan M. and Prinjha, Rab K. and Fedorov, Oleg and Burke, Rosemary and Schofield, Christopher J. and Westwood, Isaac M. and Bountra, Chas and Müller, Susanne and Van Montfort, Rob L.M. and Brennan, Paul E. and Blagg, Julian},
 doi = {10.1021/acs.jmedchem.5b01635},
 journal = {Journal of Medicinal Chemistry},
 number = {4}
}

We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.

@article{
 title = {Identification and Development of 2,3-Dihydropyrrolo[1,2-a]quinazolin-5(1H)-one Inhibitors Targeting Bromodomains within the Switch/Sucrose Nonfermenting Complex},
 type = {article},
 year = {2016},
 pages = {5095-5101},
 volume = {59},
 websites = {http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b01997},
 id = {839a3631-b6a7-392a-bc9e-8eba7e7ec906},
 created = {2016-05-23T17:04:23.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:50.647Z},
 read = {true},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Sutherell2016},
 private_publication = {false},
 abstract = {Bromodomain containing proteins PB1, SMARCA4, and SMARCA2 are important components of SWI/SNF chromatin remodeling complexes. We identified bromodomain inhibitors that target these proteins and display unusual binding modes involving water displacement from the KAc binding site. The best compound binds the fifth bromodomain of PB1 with a KD of 124 nM, SMARCA2B and SMARCA4 with KD values of 262 and 417 nM, respectively, and displays excellent selectivity over bromodomains other than PB1, SMARCA2, and SMARCA4.},
 bibtype = {article},
 author = {Sutherell, Charlotte L. and Tallant, Cynthia and Monteiro, Octovia P. and Yapp, Clarence and Fuchs, Julian E. and Fedorov, Oleg and Siejka, Paulina and Müller, Suzanne and Knapp, Stefan and Brenton, James D. and Brennan, Paul E. and Ley, Steven V.},
 doi = {10.1021/acs.jmedchem.5b01997},
 journal = {Journal of Medicinal Chemistry},
 number = {10}
}

Bromodomain containing proteins PB1, SMARCA4, and SMARCA2 are important components of SWI/SNF chromatin remodeling complexes. We identified bromodomain inhibitors that target these proteins and display unusual binding modes involving water displacement from the KAc binding site. The best compound binds the fifth bromodomain of PB1 with a KD of 124 nM, SMARCA2B and SMARCA4 with KD values of 262 and 417 nM, respectively, and displays excellent selectivity over bromodomains other than PB1, SMARCA2, and SMARCA4.

@article{
 title = {Deciphering the true antiproliferative target of an MK2 activation inhibitor in glioblastoma},
 type = {article},
 year = {2016},
 pages = {e2069},
 volume = {7},
 websites = {http://www.nature.com/doifinder/10.1038/cddis.2015.384},
 publisher = {Nature Publishing Group},
 id = {d467d2af-a598-337a-a692-7e6735d524ff},
 created = {2016-05-23T17:04:23.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:50.565Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Brennan2016},
 private_publication = {false},
 bibtype = {article},
 author = {Brennan, P. E.},
 doi = {10.1038/cddis.2015.384},
 journal = {Cell death & disease},
 number = {1}
}

@article{
 title = {Recent Progress in Histone Demethylase Inhibitors},
 type = {article},
 year = {2016},
 keywords = {Amino Acid Sequence,Animals,Drug Discovery,Enzyme Inhibitors,Histone Demethylases,Humans,Models, Molecular,Molecular Sequence Data,Peptides,Small Molecule Libraries},
 pages = {1308-1329},
 volume = {59},
 month = {2},
 id = {187a85c8-5970-363b-beaa-7b269952aca5},
 created = {2016-12-01T10:12:01.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:50.287Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {McAllister2016},
 source_type = {JOUR},
 private_publication = {false},
 abstract = {There is increasing interest in targeting histone N-methyl-lysine demethylases (KDM) with small molecules both for the generation of probes for target exploration and for therapeutic purposes. Here we update on previous reviews on the inhibition of the lysine-specific demethylases (LSDs or KDM1s) and JmjC families of N-methyl-lysine demethylases (JmjC KDMs, KDM2-7) focusing on the academic and patent literature from 2014 to date. We also highlight recent biochemical, biological and structural studies which are relevant to KDM inhibitor development.},
 bibtype = {article},
 author = {McAllister, Tom E. and England, Katherine S. and Hopkinson, Richard J. and Brennan, Paul E. and Kawamura, Akane and Schofield, Christopher J.},
 doi = {10.1021/acs.jmedchem.5b01758},
 journal = {Journal of Medicinal Chemistry},
 number = {4}
}

There is increasing interest in targeting histone N-methyl-lysine demethylases (KDM) with small molecules both for the generation of probes for target exploration and for therapeutic purposes. Here we update on previous reviews on the inhibition of the lysine-specific demethylases (LSDs or KDM1s) and JmjC families of N-methyl-lysine demethylases (JmjC KDMs, KDM2-7) focusing on the academic and patent literature from 2014 to date. We also highlight recent biochemical, biological and structural studies which are relevant to KDM inhibitor development.

@article{
 title = {Development of Selective CBP/P300 Benzoxazepine Bromodomain Inhibitors},
 type = {article},
 year = {2016},
 pages = {8889-8912},
 volume = {59},
 month = {9},
 day = {27},
 id = {7b4ab9b6-f764-3a45-806b-26918b973984},
 created = {2016-12-01T10:12:01.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:50.285Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Popp2016},
 source_type = {JOUR},
 private_publication = {false},
 abstract = {CBP (CREB (cAMP responsive element binding protein) binding protein (CREBBP)) and P300 (adenovirus E1A-associated 300 kDa protein) are two closely related histone acetyltransferases (HATs) that play a key role in the regulation of gene transcription. Both proteins contain a bromodomain flanking the HAT catalytic domain that is important for the targeting of CBP/P300 to chromatin and which offeres an opportunity for the development of protein–protein interaction inhibitors. Here we present the development of CBP/P300 bromodomain inhibitors with 2,3,4,5-tetrahydro-1,4-benzoxazepine backbone, an N-acetyl-lysine mimetic scaffold that led to the recent development of the chemical probe I-CBP112. We present comprehensive SAR of this inhibitor class as well as demonstration of cellular on target activity of the most potent and selective inhibitor TPOP146, which showed 134 nM affinity for CBP with excellent selectivity over other bromodomains.},
 bibtype = {article},
 author = {Popp, Tobias A. and Tallant, Cynthia and Rogers, Catherine and Fedorov, Oleg and Brennan, Paul E. and Müller, Susanne and Knapp, Stefan and Bracher, Franz},
 doi = {10.1021/acs.jmedchem.6b00774},
 journal = {Journal of Medicinal Chemistry},
 number = {19}
}

CBP (CREB (cAMP responsive element binding protein) binding protein (CREBBP)) and P300 (adenovirus E1A-associated 300 kDa protein) are two closely related histone acetyltransferases (HATs) that play a key role in the regulation of gene transcription. Both proteins contain a bromodomain flanking the HAT catalytic domain that is important for the targeting of CBP/P300 to chromatin and which offeres an opportunity for the development of protein–protein interaction inhibitors. Here we present the development of CBP/P300 bromodomain inhibitors with 2,3,4,5-tetrahydro-1,4-benzoxazepine backbone, an N-acetyl-lysine mimetic scaffold that led to the recent development of the chemical probe I-CBP112. We present comprehensive SAR of this inhibitor class as well as demonstration of cellular on target activity of the most potent and selective inhibitor TPOP146, which showed 134 nM affinity for CBP with excellent selectivity over other bromodomains.

@article{
 title = {Exploring the role of water in molecular recognition: Predicting protein ligandability using a combinatorial search of surface hydration sites},
 type = {article},
 year = {2016},
 keywords = {bromodomains,drug discovery,hydration,ligandability,molecular recognition,proteins,water},
 pages = {344007},
 volume = {28},
 month = {7},
 day = {1},
 id = {25682032-01ce-327f-97ca-5e6e057cdb09},
 created = {2016-12-01T10:12:01.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:49.467Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Vukovic2016},
 source_type = {JOUR},
 private_publication = {false},
 abstract = {The interaction between any two biological molecules must compete with their interaction with water molecules. This makes water the most important molecule in medicine, as it controls the interactions of every therapeutic with its target. A small molecule binding to a protein is able to recognize a unique binding site on a protein by displacing bound water molecules from specific hydration sites. Quantifying the interactions of these water molecules allows us to estimate the potential of the protein to bind a small molecule. This is referred to as ligandability. In the study, we describe a method to predict ligandability by performing a search of all possible combinations of hydration sites on protein surfaces. We predict ligandability as the summed binding free energy for each of the constituent hydration sites, computed using inhomogeneous fluid solvation theory. We compared the predicted ligandability with the maximum observed binding affinity for 20 proteins in the human bromodomain family. Based on this comparison, it was determined that effective inhibitors have been developed for the majority of bromodomains, in the range from 10 to 100 nM. However, we predict that more potent inhibitors can be developed for the bromodomains BPTF and BRD7 with relative ease, but that further efforts to develop inhibitors for ATAD2 will be extremely challenging. We have also made predictions for the 14 bromodomains with no reported small molecule K d values by isothermal titration calorimetry. The calculations predict that PBRM1(1) will be a challenging target, while others such as TAF1L(2), PBRM1(4) and TAF1(2), should be highly ligandable. As an outcome of this work, we assembled a database of experimental maximal K d that can serve as a community resource assisting medicinal chemistry efforts focused on BRDs. Effective prediction of ligandability would be a very useful tool in the drug discovery process.},
 bibtype = {article},
 author = {Vukovic, Sinisa and Brennan, Paul E. and Huggins, David J.},
 doi = {10.1088/0953-8984/28/34/344007},
 journal = {Journal of Physics Condensed Matter},
 number = {34}
}

The interaction between any two biological molecules must compete with their interaction with water molecules. This makes water the most important molecule in medicine, as it controls the interactions of every therapeutic with its target. A small molecule binding to a protein is able to recognize a unique binding site on a protein by displacing bound water molecules from specific hydration sites. Quantifying the interactions of these water molecules allows us to estimate the potential of the protein to bind a small molecule. This is referred to as ligandability. In the study, we describe a method to predict ligandability by performing a search of all possible combinations of hydration sites on protein surfaces. We predict ligandability as the summed binding free energy for each of the constituent hydration sites, computed using inhomogeneous fluid solvation theory. We compared the predicted ligandability with the maximum observed binding affinity for 20 proteins in the human bromodomain family. Based on this comparison, it was determined that effective inhibitors have been developed for the majority of bromodomains, in the range from 10 to 100 nM. However, we predict that more potent inhibitors can be developed for the bromodomains BPTF and BRD7 with relative ease, but that further efforts to develop inhibitors for ATAD2 will be extremely challenging. We have also made predictions for the 14 bromodomains with no reported small molecule K d values by isothermal titration calorimetry. The calculations predict that PBRM1(1) will be a challenging target, while others such as TAF1L(2), PBRM1(4) and TAF1(2), should be highly ligandable. As an outcome of this work, we assembled a database of experimental maximal K d that can serve as a community resource assisting medicinal chemistry efforts focused on BRDs. Effective prediction of ligandability would be a very useful tool in the drug discovery process.

@article{
 title = {BET inhibition as a new strategy for the treatment of gastric cancer},
 type = {article},
 year = {2016},
 pages = {43997-44012},
 volume = {7},
 websites = {http://www.oncotarget.com/fulltext/9766},
 month = {6},
 id = {fddfe7f3-8f83-38f6-8595-b76dceefbd3f},
 created = {2016-12-01T10:12:01.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:49.581Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Montenegro2016},
 source_type = {JOUR},
 private_publication = {false},
 abstract = {Gastric cancer is one of the most common malignancies and a leading cause of cancer death worldwide. The prognosis of stomach cancer is generally poor as this cancer is not very sensitive to commonly used chemotherapies. Epigenetic modifications play a key role in gastric cancer and contribute to the development and progression of this malignancy. In order to explore new treatment options in this target area we have screened a library of epigenetic inhibitors against gastric cancer cell lines and identified inhibitors for the BET family of bromodomains as potent inhibitors of gastric cancer cell proliferations. Here we show that both the pan-BET inhibitor (+)-JQ1 as well as a newly developed specific isoxazole inhibitor, PNZ5, showed potent inhibition of gastric cancer cell growth. Intriguingly, we found differences in the antiproliferative response between gastric cancer cells tested derived from Brazilian patients as compared to those from Asian patients, the latter being largely resistant to BET inhibition. As BET inhibitors are entering clinical trials these findings provide the first starting point for future therapies targeting gastric cancer.},
 bibtype = {article},
 author = {Montenegro, Raquel C. and Clark, Peter G.K. and Howarth, Alison and Wan, Xiao and Ceroni, Alessandro and Siejka, Paulina and Nunez-Alonso, Graciela A. and Monteiro, Octovia and Rogers, Catherine and Gamble, Vicki and Burbano, Rommel and Brennan, Paul E. and Tallant, Cynthia and Ebner, Daniel and Fedorov, Oleg and O'Neill, Eric and Knapp, Stefan and Dixon, Darren and Müller, Susanne},
 doi = {10.18632/oncotarget.9766},
 journal = {Oncotarget},
 number = {28}
}

Gastric cancer is one of the most common malignancies and a leading cause of cancer death worldwide. The prognosis of stomach cancer is generally poor as this cancer is not very sensitive to commonly used chemotherapies. Epigenetic modifications play a key role in gastric cancer and contribute to the development and progression of this malignancy. In order to explore new treatment options in this target area we have screened a library of epigenetic inhibitors against gastric cancer cell lines and identified inhibitors for the BET family of bromodomains as potent inhibitors of gastric cancer cell proliferations. Here we show that both the pan-BET inhibitor (+)-JQ1 as well as a newly developed specific isoxazole inhibitor, PNZ5, showed potent inhibition of gastric cancer cell growth. Intriguingly, we found differences in the antiproliferative response between gastric cancer cells tested derived from Brazilian patients as compared to those from Asian patients, the latter being largely resistant to BET inhibition. As BET inhibitors are entering clinical trials these findings provide the first starting point for future therapies targeting gastric cancer.

@article{
 title = {Structure of the Human Protein Kinase ZAK in Complex with Vemurafenib},
 type = {article},
 year = {2016},
 pages = {1595-1602},
 volume = {11},
 month = {6},
 id = {b81edb7e-417b-3293-97cd-144864b2073c},
 created = {2016-12-01T10:12:01.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:49.588Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Mathea2016},
 source_type = {JOUR},
 private_publication = {false},
 abstract = {The mixed lineage kinase ZAK is a key regulator of the MAPK pathway mediating cell survival and inflammatory response. ZAK is targeted by several clinically approved kinase inhibitors, and inhibition of ZAK has been reported to protect from doxorubicin-induced cardiomyopathy. On the other hand, unintended targeting of ZAK has been linked to severe adverse effects such as the development of cutaneous squamous cell carcinoma. Therefore, both specific inhibitors of ZAK, as well as anticancer drugs lacking off-target activity against ZAK, may provide therapeutic benefit. Here we report the first crystal structure of ZAK in complex with the B-RAF inhibitor vemurafenib. The co-crystal structure displayed a number of ZAK specific features including a highly distorted P loop conformation enabling rational inhibitor design. Positional scanning peptide library analysis revealed a unique substrate specificity of the ZAK kinase including unprecedented preferences for histidine residues at positions 1 and +2 relative to the phosphoacceptor site. In addition, we screened a library of clinical kinase inhibitors identifying several inhibitors that potently inhibit ZAK, demonstrating that this kinase is commonly mistargeted by currently used anticancer drugs.},
 bibtype = {article},
 author = {Mathea, Sebastian and Abdul Azeez, Kamal R. and Salah, Eidarus and Tallant, Cynthia and Wolfreys, Finn and Konietzny, Rebecca and Fischer, Roman and Lou, Hua Jane and Brennan, Paul E. and Schnapp, Gisela and Pautsch, Alexander and Kessler, Benedikt M. and Turk, Benjamin E. and Knapp, Stefan},
 doi = {10.1021/acschembio.6b00043},
 journal = {ACS Chemical Biology},
 number = {6}
}

The mixed lineage kinase ZAK is a key regulator of the MAPK pathway mediating cell survival and inflammatory response. ZAK is targeted by several clinically approved kinase inhibitors, and inhibition of ZAK has been reported to protect from doxorubicin-induced cardiomyopathy. On the other hand, unintended targeting of ZAK has been linked to severe adverse effects such as the development of cutaneous squamous cell carcinoma. Therefore, both specific inhibitors of ZAK, as well as anticancer drugs lacking off-target activity against ZAK, may provide therapeutic benefit. Here we report the first crystal structure of ZAK in complex with the B-RAF inhibitor vemurafenib. The co-crystal structure displayed a number of ZAK specific features including a highly distorted P loop conformation enabling rational inhibitor design. Positional scanning peptide library analysis revealed a unique substrate specificity of the ZAK kinase including unprecedented preferences for histidine residues at positions 1 and +2 relative to the phosphoacceptor site. In addition, we screened a library of clinical kinase inhibitors identifying several inhibitors that potently inhibit ZAK, demonstrating that this kinase is commonly mistargeted by currently used anticancer drugs.

@article{
 title = {Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit},
 type = {article},
 year = {2016},
 pages = {4800-4811},
 volume = {59},
 month = {5},
 id = {a06dd1db-fd7a-398d-a4d8-4c698664dd35},
 created = {2016-12-01T10:12:01.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:49.663Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Gerstenberger2016},
 source_type = {JOUR},
 private_publication = {false},
 abstract = {The acetyl post-translational modification of chromatin at selected histone lysine residues is interpreted by an acetyl-lysine specific interaction with bromodomain reader modules. Here we report the discovery of the potent, acetyl-lysine competitive and cell active inhibitor PFI-3 that binds to certain Family VIII bromodomains while displaying significant, broader bromodomain family selectivity. The high specificity of PFI-3 for Family VIII was achieved through a novel bromodomain binding mode of a phenolic head group that led to the unusual displacement of water molecules that are generally retained by most other bromodomain inhibitors reported to date. The medicinal chemistry program that led to PFI-3 from an initial fragment screening hit is described in detail and additional analogues with differing Family VIII bromodomain selectivity profiles are also reported. We also describe the full pharmacological characterization of PFI-3 as a chemical probe, including data from adipocyte and myoblast and cell differentiation assays.},
 bibtype = {article},
 author = {Gerstenberger, Brian S. and Trzupek, John D. and Tallant, Cynthia and Fedorov, Oleg and Filippakopoulos, Panagis and Brennan, Paul E. and Fedele, Vita and Martin, Sarah and Picaud, Sarah and Rogers, Catherine and Parikh, Mihir and Taylor, Alexandria and Samas, Brian and O'Mahony, Alison and Berg, Ellen and Pallares, Gabriel and Torrey, Adam D. and Treiber, Daniel K. and Samardjiev, Ivan J. and Nasipak, Brian T. and Padilla-Benavides, Teresita and Wu, Qiong and Imbalzano, Anthony N. and Nickerson, Jeffrey A. and Bunnage, Mark E. and Müller, Susanne and Knapp, Stefan and Owen, Dafydd R.},
 doi = {10.1021/acs.jmedchem.6b00012},
 journal = {Journal of Medicinal Chemistry},
 number = {10}
}

The acetyl post-translational modification of chromatin at selected histone lysine residues is interpreted by an acetyl-lysine specific interaction with bromodomain reader modules. Here we report the discovery of the potent, acetyl-lysine competitive and cell active inhibitor PFI-3 that binds to certain Family VIII bromodomains while displaying significant, broader bromodomain family selectivity. The high specificity of PFI-3 for Family VIII was achieved through a novel bromodomain binding mode of a phenolic head group that led to the unusual displacement of water molecules that are generally retained by most other bromodomain inhibitors reported to date. The medicinal chemistry program that led to PFI-3 from an initial fragment screening hit is described in detail and additional analogues with differing Family VIII bromodomain selectivity profiles are also reported. We also describe the full pharmacological characterization of PFI-3 as a chemical probe, including data from adipocyte and myoblast and cell differentiation assays.

@article{
 title = {Structural analysis of human KDM5B guides histone demethylase inhibitor development chem. comp.},
 type = {article},
 year = {2016},
 pages = {78-80},
 volume = {12},
 websites = {http://www.nature.com/doifinder/10.1038/nchembio.2087},
 month = {7},
 id = {9064919a-50c8-3300-82eb-94751449c459},
 created = {2016-12-01T10:12:01.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:49.427Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Johansson2016},
 source_type = {JOUR},
 private_publication = {false},
 abstract = {Members of the KDM5 (also known as JARID1) family are 2-oxoglutarate- and Fe(2+)-dependent oxygenases that act as histone H3K4 demethylases, thereby regulating cell proliferation and stem cell self-renewal and differentiation. Here we report crystal structures of the catalytic core of the human KDM5B enzyme in complex with three inhibitor chemotypes. These scaffolds exploit several aspects of the KDM5 active site, and their selectivity profiles reflect their hybrid features with respect to the KDM4 and KDM6 families. Whereas GSK-J1, a previously identified KDM6 inhibitor, showed about sevenfold less inhibitory activity toward KDM5B than toward KDM6 proteins, KDM5-C49 displayed 25-100-fold selectivity between KDM5B and KDM6B. The cell-permeable derivative KDM5-C70 had an antiproliferative effect in myeloma cells, leading to genome-wide elevation of H3K4me3 levels. The selective inhibitor GSK467 exploited unique binding modes, but it lacked cellular potency in the myeloma system. Taken together, these structural leads deliver multiple starting points for further rational and selective inhibitor design.},
 bibtype = {article},
 author = {Johansson, Catrine and Velupillai, Srikannathasan and Tumber, Anthony and Szykowska, Aleksandra and Hookway, Edward S and Nowak, Radoslaw P and Strain-Damerell, Claire and Gileadi, Carina and Philpott, Martin and Burgess-Brown, Nicola and Wu, Na and Kopec, Jola and Nuzzi, Andrea and Steuber, Holger and Egner, Ursula and Badock, Volker and Munro, Shonagh and LaThangue, Nicholas B and Westaway, Sue and Brown, Jack and Athanasou, Nick and Prinjha, Rab and Brennan, Paul E and Oppermann, Udo},
 doi = {10.1038/nchembio.2087},
 journal = {Nature Chemical Biology},
 number = {8}
}

Members of the KDM5 (also known as JARID1) family are 2-oxoglutarate- and Fe(2+)-dependent oxygenases that act as histone H3K4 demethylases, thereby regulating cell proliferation and stem cell self-renewal and differentiation. Here we report crystal structures of the catalytic core of the human KDM5B enzyme in complex with three inhibitor chemotypes. These scaffolds exploit several aspects of the KDM5 active site, and their selectivity profiles reflect their hybrid features with respect to the KDM4 and KDM6 families. Whereas GSK-J1, a previously identified KDM6 inhibitor, showed about sevenfold less inhibitory activity toward KDM5B than toward KDM6 proteins, KDM5-C49 displayed 25-100-fold selectivity between KDM5B and KDM6B. The cell-permeable derivative KDM5-C70 had an antiproliferative effect in myeloma cells, leading to genome-wide elevation of H3K4me3 levels. The selective inhibitor GSK467 exploited unique binding modes, but it lacked cellular potency in the myeloma system. Taken together, these structural leads deliver multiple starting points for further rational and selective inhibitor design.

@article{
 title = {Development of chemical probes for the bromodomains of BRD7 and BRD9},
 type = {article},
 year = {2016},
 pages = {73-80},
 volume = {19},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/27769361},
 month = {3},
 city = {England},
 id = {077fbf48-1e1e-3ea8-9b59-df6a9526e0fe},
 created = {2016-12-01T10:12:02.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:46.443Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Clark2016},
 source_type = {JOUR},
 private_publication = {false},
 abstract = {The bromodomain family of proteins are ‘readers’ of acetylated lysines of histones, a key mark in the epigenetic code of gene regulation. Without high quality chemical probes with which to study these proteins, their biological function, and potential use in therapeutics, remains unknown. Recently, a number of chemical ligands were reported for the previously unprobed bromodomain proteins BRD7 and BRD9. Herein the development and characterisation of probes against these proteins is detailed, including the preliminary biological activity of BRD7 and BRD9 assessed using these probes. Future studies utilising these chemically-diverse compounds in parallel will allow for a confident assessment of the role of BRD7/9, and give multiple entry points into any subsequent pharmaceutical programs.},
 bibtype = {article},
 author = {Clark, Peter G.K. and Dixon, Darren J. and Brennan, Paul E.},
 doi = {10.1016/j.ddtec.2016.05.002},
 journal = {Drug Discovery Today: Technologies}
}

The bromodomain family of proteins are ‘readers’ of acetylated lysines of histones, a key mark in the epigenetic code of gene regulation. Without high quality chemical probes with which to study these proteins, their biological function, and potential use in therapeutics, remains unknown. Recently, a number of chemical ligands were reported for the previously unprobed bromodomain proteins BRD7 and BRD9. Herein the development and characterisation of probes against these proteins is detailed, including the preliminary biological activity of BRD7 and BRD9 assessed using these probes. Future studies utilising these chemically-diverse compounds in parallel will allow for a confident assessment of the role of BRD7/9, and give multiple entry points into any subsequent pharmaceutical programs.

@article{
 title = {Chemical probes and inhibitors of bromodomains outside the BET family},
 type = {article},
 year = {2016},
 pages = {2246-2264},
 volume = {7},
 websites = {http://xlink.rsc.org/?DOI=C6MD00373G},
 publisher = {The Royal Society of Chemistry},
 id = {a478c148-46db-364c-bed6-65a8f304f3de},
 created = {2017-03-08T13:30:37.000Z},
 accessed = {2017-03-08},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:46.119Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Moustakim2016},
 private_publication = {false},
 abstract = {Mathematical sciences and computational methods have found new applications in fi elds like medicine over the last few decades. Modern data acquisition and data analysis protocols have been of great assistance to medical researchers and clinical scientists. Especially in psychiatry, technology and science have made new computational methods available to assist the development of predictive modeling and to identify diseases more accurately. Data mining (or knowledge discovery) aims to extract information from large datasets and solve challenging tasks, like patient assessment, early mental disease diagnosis, and drug effi - cacy assessment. Accurate and fast data analysis methods are very important, especially when dealing with severe psychiatric diseases like schizophrenia. In this paper, we focus on computational methods related to data analysis and more specifi cally to data mining. Then, we discuss some related research in the fi eld of psychiatry.},
 bibtype = {article},
 author = {Moustakim, Moses and Clark, Peter G.K. and Hay, Duncan A. and Dixon, Darren J. and Brennan, Paul E.},
 doi = {10.1039/c6md00373g},
 journal = {MedChemComm},
 number = {12}
}

Mathematical sciences and computational methods have found new applications in fi elds like medicine over the last few decades. Modern data acquisition and data analysis protocols have been of great assistance to medical researchers and clinical scientists. Especially in psychiatry, technology and science have made new computational methods available to assist the development of predictive modeling and to identify diseases more accurately. Data mining (or knowledge discovery) aims to extract information from large datasets and solve challenging tasks, like patient assessment, early mental disease diagnosis, and drug effi - cacy assessment. Accurate and fast data analysis methods are very important, especially when dealing with severe psychiatric diseases like schizophrenia. In this paper, we focus on computational methods related to data analysis and more specifi cally to data mining. Then, we discuss some related research in the fi eld of psychiatry.

@article{
 title = {Promiscuous targeting of bromodomains by bromosporine identifies BET proteins as master regulators of primary transcription response in leukemia},
 type = {article},
 year = {2016},
 keywords = {BET,Bromodomains,epigenetics,inhibition,leukemias},
 pages = {e1600760},
 volume = {2},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/27757418,http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC5061470},
 month = {10},
 publisher = {American Association for the Advancement of Science},
 id = {03c9aebd-20aa-3fc0-bb47-45cf5a1bc443},
 created = {2017-05-29T11:11:26.381Z},
 accessed = {2017-05-29},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:48.727Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Picaud2016},
 private_publication = {false},
 abstract = {Bromodomains (BRDs) have emerged as compelling targets for cancer therapy. The development of selective and potent BET (bromo and extra-terminal) inhibitors and their significant activity in diverse tumor models have rapidly translated into clinical studies and have motivated drug development efforts targeting non-BET BRDs. However, the complex multidomain/subunit architecture of BRD protein complexes complicates predictions of the consequences of their pharmacological targeting. To address this issue, we developed a promiscuous BRD inhibitor [bromosporine (BSP)] that broadly targets BRDs (including BETs) with nanomolar affinity, creating a tool for the identification of cellular processes and diseases where BRDs have a regulatory function. As a proof of principle, we studied the effects of BSP on leukemic cell lines known to be sensitive to BET inhibition and found, as expected, strong antiproliferative activity. Comparison of the modulation of transcriptional profiles by BSP after a short exposure to the inhibitor resulted in a BET inhibitor signature but no significant additional changes in transcription that could account for inhibition of other BRDs. Thus, nonselective targeting of BRDs identified BETs, but not other BRDs, as master regulators of context-dependent primary transcription response.},
 bibtype = {article},
 author = {Picaud, Sarah and Leonards, Katharina and Lambert, Jean Philippe and Dovey, Oliver and Wells, Christopher and Fedorov, Oleg and Monteiro, Octovia and Fujisawa, Takao and Wang, Chen Yi and Lingard, Hannah and Tallant, Cynthia and Nikbin, Nikzad and Guetzoyan, Lucie and Ingham, Richard and Ley, Steven V. and Brennan, Paul and Muller, Susanne and Samsonova, Anastasia and Gingras, Anne Claude and Schwaller, Juerg and Vassiliou, George and Knapp, Stefan and Filippakopoulos, Panagis},
 doi = {10.1126/sciadv.1600760},
 journal = {Science Advances},
 number = {10}
}

Bromodomains (BRDs) have emerged as compelling targets for cancer therapy. The development of selective and potent BET (bromo and extra-terminal) inhibitors and their significant activity in diverse tumor models have rapidly translated into clinical studies and have motivated drug development efforts targeting non-BET BRDs. However, the complex multidomain/subunit architecture of BRD protein complexes complicates predictions of the consequences of their pharmacological targeting. To address this issue, we developed a promiscuous BRD inhibitor [bromosporine (BSP)] that broadly targets BRDs (including BETs) with nanomolar affinity, creating a tool for the identification of cellular processes and diseases where BRDs have a regulatory function. As a proof of principle, we studied the effects of BSP on leukemic cell lines known to be sensitive to BET inhibition and found, as expected, strong antiproliferative activity. Comparison of the modulation of transcriptional profiles by BSP after a short exposure to the inhibitor resulted in a BET inhibitor signature but no significant additional changes in transcription that could account for inhibition of other BRDs. Thus, nonselective targeting of BRDs identified BETs, but not other BRDs, as master regulators of context-dependent primary transcription response.

@misc{
 title = {Advances and challenges in understanding histone demethylase biology},
 type = {misc},
 year = {2016},
 source = {Current Opinion in Chemical Biology},
 pages = {151-159},
 volume = {33},
 id = {bbe251ae-9ad6-3e5c-a3a5-8a09f08c6c13},
 created = {2017-11-28T02:10:04.319Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:49.952Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Nowak2016},
 private_publication = {false},
 abstract = {Within the last decade we have witnessed significant progress in the field of chromatin methylation, ranging from the discovery that chromatin methylation is reversible, to the identification of two classes of oxidative chromatin demethylases. Multiple genetic and cellular studies emphasize the role of members of the amine oxidase and 2-oxoglutarate oxygenase enzyme families involved in methyl-lysine in physiology and disease. Advances in understanding of the underlying biochemistry have resulted in development of first series of clinical inhibitors and tool compounds which continue to resolve and help understand the complex relationships between chromatin modification, control of gene expression and metabolic states.},
 bibtype = {misc},
 author = {Nowak, Radoslaw P. and Tumber, Anthony and Johansson, Catrine and Che, Ka Hing and Brennan, Paul and Owen, Dafydd and Oppermann, Udo},
 doi = {10.1016/j.cbpa.2016.06.021}
}

Within the last decade we have witnessed significant progress in the field of chromatin methylation, ranging from the discovery that chromatin methylation is reversible, to the identification of two classes of oxidative chromatin demethylases. Multiple genetic and cellular studies emphasize the role of members of the amine oxidase and 2-oxoglutarate oxygenase enzyme families involved in methyl-lysine in physiology and disease. Advances in understanding of the underlying biochemistry have resulted in development of first series of clinical inhibitors and tool compounds which continue to resolve and help understand the complex relationships between chromatin modification, control of gene expression and metabolic states.

@phdthesis{
 title = {A potent and selective inhibitor of a histone demethylase},
 type = {phdthesis},
 year = {2016},
 institution = {University of Oxford},
 department = {Chemistry Department},
 id = {7c58cf99-e61f-3f30-9fef-90f1026719ec},
 created = {2020-01-20T12:44:26.379Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2020-01-20T12:44:26.379Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 private_publication = {false},
 bibtype = {phdthesis},
 author = {England, Katherine S.}
}

@article{
 title = {The promise and peril of chemical probes},
 type = {article},
 year = {2015},
 pages = {536-541},
 volume = {11},
 websites = {http://dx.doi.org/10.1038/nchembio.1867,http://www.nature.com/nchembio/journal/v11/n8/pdf/nchembio.1867.pdf},
 publisher = {Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.},
 id = {717636c8-bc52-313a-9f70-f72f9d105bd0},
 created = {2015-10-01T17:18:08.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:50.164Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Arrowsmith2015a},
 source_type = {Journal Article},
 private_publication = {false},
 abstract = {Chemical probes are powerful reagents with increasing impacts on biomedical research. However, probes of poor quality or that are used incorrectly generate misleading results. To help address these shortcomings, we will create a community-driven wiki resource to improve quality and convey current best practice.},
 bibtype = {article},
 author = {Arrowsmith, Cheryl H. and Audia, James E. and Austin, Christopher and Baell, Jonathan and Bennett, Jonathan and Blagg, Julian and Bountra, Chas and Brennan, Paul E. and Brown, Peter J. and Bunnage, Mark E. and Buser-Doepner, Carolyn and Campbell, Robert M. and Carter, Adrian J. and Cohen, Philip and Copeland, Robert A. and Cravatt, Ben and Dahlin, Jayme L. and Dhanak, Dashyant and Edwards, Aled M. and Frye, Stephen V. and Gray, Nathanael and Grimshaw, Charles E. and Hepworth, David and Howe, Trevor and Huber, Kilian V.M. and Jin, Jian and Knapp, Stefan and Kotz, Joanne D. and Kruger, Ryan G. and Lowe, Derek and Mader, Mary M. and Marsden, Brian and Mueller-Fahrnow, Anke and Müller, Susanne and O'Hagan, Ronan C. and Overington, John P. and Owen, Dafydd R. and Rosenberg, Saul H. and Roth, Brian and Ross, Ruth and Schapira, Matthieu and Schreiber, Stuart L. and Shoichet, Brian and Sundström, Michael and Superti-Furga, Giulio and Taunton, Jack and Toledo-Sherman, Leticia and Walpole, Chris and Walters, Michael A. and Willson, Timothy M. and Workman, Paul and Young, Robert N. and Zuercher, William J.},
 doi = {10.1038/nchembio.1867},
 journal = {Nature Chemical Biology},
 number = {8}
}

Chemical probes are powerful reagents with increasing impacts on biomedical research. However, probes of poor quality or that are used incorrectly generate misleading results. To help address these shortcomings, we will create a community-driven wiki resource to improve quality and convey current best practice.

@article{
 title = {CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses},
 type = {article},
 year = {2015},
 pages = {10768-10773},
 volume = {112},
 websites = {http://www.pnas.org/lookup/doi/10.1073/pnas.1501956112},
 id = {86990447-b226-3c97-8230-0dadd0c1a111},
 created = {2015-10-01T17:18:12.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:49.235Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Hammitzsch2015},
 source_type = {Journal Article},
 private_publication = {false},
 abstract = {Th17 responses are critical to a variety of human autoimmune diseases, and therapeutic targeting with monoclonal antibodies against IL-17 and IL-23 has shown considerable promise. Here, we report data to support selective bromodomain blockade of the transcriptional coactivators CBP (CREB binding protein) and p300 as an alternative approach to inhibit human Th17 responses. We show that CBP30 has marked molecular specificity for the bromodomains of CBP and p300, compared with 43 other bromodomains. In unbiased cellular testing on a diverse panel of cultured primary human cells, CBP30 reduced immune cell production of IL-17A and other proinflammatory cytokines. CBP30 also inhibited IL-17A secretion by Th17 cells from healthy donors and patients with ankylosing spondylitis and psoriatic arthritis. Transcriptional profiling of human T cells after CBP30 treatment showed a much more restricted effect on gene expression than that observed with the pan-BET (bromo and extraterminal domain protein family) bromodomain inhibitor JQ1. This selective targeting of the CBP/p300 bromodomain by CBP30 will potentially lead to fewer side effects than with the broadly acting epigenetic inhibitors currently in clinical trials.},
 bibtype = {article},
 author = {Hammitzsch, Ariane and Tallant, Cynthia and Fedorov, Oleg and O’Mahony, Alison and Brennan, Paul E. and Hay, Duncan A. and Martinez, Fernando O. and Al-Mossawi, M. Hussein and de Wit, Jelle and Vecellio, Matteo and Wells, Christopher and Wordsworth, Paul and Müller, Susanne and Knapp, Stefan and Bowness, Paul},
 doi = {10.1073/pnas.1501956112},
 journal = {Proceedings of the National Academy of Sciences},
 number = {34}
}

Th17 responses are critical to a variety of human autoimmune diseases, and therapeutic targeting with monoclonal antibodies against IL-17 and IL-23 has shown considerable promise. Here, we report data to support selective bromodomain blockade of the transcriptional coactivators CBP (CREB binding protein) and p300 as an alternative approach to inhibit human Th17 responses. We show that CBP30 has marked molecular specificity for the bromodomains of CBP and p300, compared with 43 other bromodomains. In unbiased cellular testing on a diverse panel of cultured primary human cells, CBP30 reduced immune cell production of IL-17A and other proinflammatory cytokines. CBP30 also inhibited IL-17A secretion by Th17 cells from healthy donors and patients with ankylosing spondylitis and psoriatic arthritis. Transcriptional profiling of human T cells after CBP30 treatment showed a much more restricted effect on gene expression than that observed with the pan-BET (bromo and extraterminal domain protein family) bromodomain inhibitor JQ1. This selective targeting of the CBP/p300 bromodomain by CBP30 will potentially lead to fewer side effects than with the broadly acting epigenetic inhibitors currently in clinical trials.

@article{
 title = {Generation of a selective small molecule inhibitor of the CBP/p300 bromodomain for Leukemia therapy},
 type = {article},
 year = {2015},
 pages = {5106-5119},
 volume = {75},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/26552700},
 month = {11},
 day = {9},
 id = {7a51ada6-9104-367f-aab9-8a7df3fba6f9},
 created = {2015-11-18T16:40:02.000Z},
 accessed = {2015-11-12},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:49.927Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Picaud2015},
 private_publication = {false},
 abstract = {The histone acetyltransferases CBP/p300 are involved in recurrent leukemia-associated chromosomal translocations and are key regulators of cell growth. Therefore, efforts to generate inhibitors of CBP/p300 are of clinical value. We developed a specific and potent acetyl-lysine competitive protein-protein interaction inhibitor, I-CBP112, that targets the CBP/p300 bromodomains. Exposure of human and mouse leukemic cell lines to I-CBP112 resulted in substantially impaired colony formation and induced cellular differentiation without significant cytotoxicity. I-CBP112 significantly reduced the leukemia-initiating potential of MLL-AF9+ AML cells in a dose-dependent manner in vitro and in vivo. Interestingly, I-CBP112 increased the cytotoxic activity of BET bromodomain inhibitor JQ1 as well as doxorubicin. Collectively we report the development and preclinical evaluation of a novel, potent inhibitor targeting CBP/p300 bromodomains that impairs aberrant self-renewal of leukemic cells. The synergistic effects of I-CBP112 and current standard therapy (doxorubicin) as well as emerging treatment strategies (BET inhibition) provide new opportunities for combinatorial treatment of leukemia and potentially other cancers.},
 bibtype = {article},
 author = {Picaud, Sarah and Fedorov, Oleg and Thanasopoulou, Angeliki and Leonards, Katharina and Jones, Katherine and Meier, Julia and Olzscha, Heidi and Monteiro, Octovia and Martin, Sarah and Philpott, Martin and Tumber, Anthony and Filippakopoulos, Panagis and Yapp, Clarence and Wells, Christopher and Che, Ka Hing and Bannister, Andrew and Robson, Samuel and Kumar, Umesh and Parr, Nigel and Lee, Kevin and Lugo, Dave and Jeffrey, Philip and Taylor, Simon and Vecellio, Matteo L. and Bountra, Chas and Brennan, Paul E. and O'Mahony, Alison and Velichko, Sharlene and Muller, Susanne and Hay, Duncan and Daniels, Danette L. and Urh, Marjeta and La Thangue, Nicholas B. and Kouzarides, Tony and Prinjha, Rab and Schwaller, Jurg and Knapp, Stefan},
 doi = {10.1158/0008-5472.CAN-15-0236},
 journal = {Cancer Research},
 number = {23}
}

The histone acetyltransferases CBP/p300 are involved in recurrent leukemia-associated chromosomal translocations and are key regulators of cell growth. Therefore, efforts to generate inhibitors of CBP/p300 are of clinical value. We developed a specific and potent acetyl-lysine competitive protein-protein interaction inhibitor, I-CBP112, that targets the CBP/p300 bromodomains. Exposure of human and mouse leukemic cell lines to I-CBP112 resulted in substantially impaired colony formation and induced cellular differentiation without significant cytotoxicity. I-CBP112 significantly reduced the leukemia-initiating potential of MLL-AF9+ AML cells in a dose-dependent manner in vitro and in vivo. Interestingly, I-CBP112 increased the cytotoxic activity of BET bromodomain inhibitor JQ1 as well as doxorubicin. Collectively we report the development and preclinical evaluation of a novel, potent inhibitor targeting CBP/p300 bromodomains that impairs aberrant self-renewal of leukemic cells. The synergistic effects of I-CBP112 and current standard therapy (doxorubicin) as well as emerging treatment strategies (BET inhibition) provide new opportunities for combinatorial treatment of leukemia and potentially other cancers.

@article{
 title = {Selective targeting of the BRG/PB1 bromodomains impairs embryonic and trophoblast stem cell maintenance},
 type = {article},
 year = {2015},
 pages = {e1500723},
 volume = {1},
 websites = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4681344&tool=pmcentrez&rendertype=abstract},
 month = {11},
 id = {ef78743f-1db2-3122-83ea-7002041d7fe8},
 created = {2016-01-05T09:04:19.000Z},
 accessed = {2015-12-26},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2023-08-25T17:51:16.455Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Fedorov2015},
 private_publication = {false},
 abstract = {Mammalian SWI/SNF [also called Brg/Brahma-associated factors (BAFs)] are evolutionarily conserved chromatin-remodeling complexes regulating gene transcription programs during development and stem cell differentiation. BAF complexes contain an ATP (adenosine 5'-triphosphate)-driven remodeling enzyme (either BRG1 or BRM) and multiple protein interaction domains including bromodomains, an evolutionary conserved acetyl lysine-dependent protein interaction motif that recruits transcriptional regulators to acetylated chromatin. We report a potent and cell active protein interaction inhibitor, PFI-3, that selectively binds to essential BAF bromodomains. The high specificity of PFI-3 was achieved on the basis of a novel binding mode of a salicylic acid head group that led to the replacement of water molecules typically maintained in other bromodomain inhibitor complexes. We show that exposure of embryonic stem cells to PFI-3 led to deprivation of stemness and deregulated lineage specification. Furthermore, differentiation of trophoblast stem cells in the presence of PFI-3 was markedly enhanced. The data present a key function of BAF bromodomains in stem cell maintenance and differentiation, introducing a novel versatile chemical probe for studies on acetylation-dependent cellular processes controlled by BAF remodeling complexes.},
 bibtype = {article},
 author = {Fedorov, Oleg and Castex, Josefina and Tallant, Cynthia and Owen, Dafydd R. and Martin, Sarah and Aldeghi, Matteo and Monteiro, Octovia and Filippakopoulos, Panagis and Picaud, Sarah and Trzupek, John D. and Gerstenberger, Brian S. and Bountra, Chas and Willmann, Dominica and Wells, Christopher and Philpott, Martin and Rogers, Catherine and Biggin, Philip C. and Brennan, Paul E. and Bunnage, Mark E. and Schüle, Roland and Günther, Thomas and Knapp, Stefan and Müller, Susanne},
 doi = {10.1126/sciadv.1500723},
 journal = {Science Advances},
 number = {10}
}

Mammalian SWI/SNF [also called Brg/Brahma-associated factors (BAFs)] are evolutionarily conserved chromatin-remodeling complexes regulating gene transcription programs during development and stem cell differentiation. BAF complexes contain an ATP (adenosine 5'-triphosphate)-driven remodeling enzyme (either BRG1 or BRM) and multiple protein interaction domains including bromodomains, an evolutionary conserved acetyl lysine-dependent protein interaction motif that recruits transcriptional regulators to acetylated chromatin. We report a potent and cell active protein interaction inhibitor, PFI-3, that selectively binds to essential BAF bromodomains. The high specificity of PFI-3 was achieved on the basis of a novel binding mode of a salicylic acid head group that led to the replacement of water molecules typically maintained in other bromodomain inhibitor complexes. We show that exposure of embryonic stem cells to PFI-3 led to deprivation of stemness and deregulated lineage specification. Furthermore, differentiation of trophoblast stem cells in the presence of PFI-3 was markedly enhanced. The data present a key function of BAF bromodomains in stem cell maintenance and differentiation, introducing a novel versatile chemical probe for studies on acetylation-dependent cellular processes controlled by BAF remodeling complexes.

@article{
 title = {Inflammatory Signaling by NOD-RIPK2 Is Inhibited by Clinically Relevant Type II Kinase Inhibitors},
 type = {article},
 year = {2015},
 pages = {1174-1184},
 volume = {22},
 websites = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4579271&tool=pmcentrez&rendertype=abstract},
 month = {9},
 day = {17},
 id = {e8cf465e-6b68-39b5-a45a-5349edc6a92d},
 created = {2016-01-05T09:04:59.000Z},
 accessed = {2016-01-05},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:49.339Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Canning2015},
 private_publication = {false},
 abstract = {Summary RIPK2 mediates pro-inflammatory signaling from the bacterial sensors NOD1 and NOD2, and is an emerging therapeutic target in autoimmune and inflammatory diseases. We observed that cellular RIPK2 can be potently inhibited by type II inhibitors that displace the kinase activation segment, whereas ATP-competitive type I inhibition was only poorly effective. The most potent RIPK2 inhibitors were the US Food and Drug Administration-approved drugs ponatinib and regorafenib. Their mechanism of action was independent of NOD2 interaction and involved loss of downstream kinase activation as evidenced by lack of RIPK2 autophosphorylation. Notably, these molecules also blocked RIPK2 ubiquitination and, consequently, inflammatory nuclear factor κB signaling. In monocytes, the inhibitors selectively blocked NOD-dependent tumor necrosis factor production without affecting lipopolysaccharide-dependent pathways. We also determined the first crystal structure of RIPK2 bound to ponatinib, and identified an allosteric site for inhibitor development. These results highlight the potential for type II inhibitors to treat indications of RIPK2 activation as well as inflammation-associated cancers.},
 bibtype = {article},
 author = {Canning, Peter and Ruan, Qui and Schwerd, Tobias and Hrdinka, Matous and Maki, Jenny L. and Saleh, Danish and Suebsuwong, Chalada and Ray, Soumya and Brennan, Paul E. and Cuny, Gregory D. and Uhlig, Holm H. and Gyrd-Hansen, Mads and Degterev, Alexei and Bullock, Alex N.},
 doi = {10.1016/j.chembiol.2015.07.017},
 journal = {Chemistry and Biology},
 number = {9}
}

Summary RIPK2 mediates pro-inflammatory signaling from the bacterial sensors NOD1 and NOD2, and is an emerging therapeutic target in autoimmune and inflammatory diseases. We observed that cellular RIPK2 can be potently inhibited by type II inhibitors that displace the kinase activation segment, whereas ATP-competitive type I inhibition was only poorly effective. The most potent RIPK2 inhibitors were the US Food and Drug Administration-approved drugs ponatinib and regorafenib. Their mechanism of action was independent of NOD2 interaction and involved loss of downstream kinase activation as evidenced by lack of RIPK2 autophosphorylation. Notably, these molecules also blocked RIPK2 ubiquitination and, consequently, inflammatory nuclear factor κB signaling. In monocytes, the inhibitors selectively blocked NOD-dependent tumor necrosis factor production without affecting lipopolysaccharide-dependent pathways. We also determined the first crystal structure of RIPK2 bound to ponatinib, and identified an allosteric site for inhibitor development. These results highlight the potential for type II inhibitors to treat indications of RIPK2 activation as well as inflammation-associated cancers.

@article{
 title = {K2P channel gating mechanisms revealed by structures of TREK-2 and a complex with Prozac},
 type = {article},
 year = {2015},
 keywords = {Amino Acid Sequence,Arachidonic Acid,Arachidonic Acid: pharmacology,Binding Sites,Crystallography, X-Ray,Fluoxetine,Fluoxetine: analogs & derivatives,Fluoxetine: chemistry,Fluoxetine: metabolism,Fluoxetine: pharmacology,Humans,Ion Channel Gating,Models, Molecular,Molecular Dynamics Simulation,Molecular Sequence Data,Potassium,Potassium Channels, Tandem Pore Domain,Potassium Channels, Tandem Pore Domain: antagonist,Potassium Channels, Tandem Pore Domain: chemistry,Potassium Channels, Tandem Pore Domain: metabolism,Potassium: metabolism,Protein Conformation,Protein Folding,Protein Structure, Secondary,Protein Structure, Tertiary},
 pages = {1256-1259},
 volume = {347},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/25766236},
 month = {3},
 day = {13},
 id = {9a619900-cb4a-36b0-b68d-2e56a9be8763},
 created = {2016-01-05T09:05:54.000Z},
 accessed = {2015-11-23},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:49.379Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Dong2015},
 private_publication = {false},
 abstract = {TREK-2 (KCNK10/K2P10), a two-pore domain potassium (K2P) channel, is gated by multiple stimuli such as stretch, fatty acids, and pH and by several drugs. However, the mechanisms that control channel gating are unclear. Here we present crystal structures of the human TREK-2 channel (up to 3.4 angstrom resolution) in two conformations and in complex with norfluoxetine, the active metabolite of fluoxetine (Prozac) and a state-dependent blocker of TREK channels. Norfluoxetine binds within intramembrane fenestrations found in only one of these two conformations. Channel activation by arachidonic acid and mechanical stretch involves conversion between these states through movement of the pore-lining helices. These results provide an explanation for TREK channel mechanosensitivity, regulation by diverse stimuli, and possible off-target effects of the serotonin reuptake inhibitor Prozac.},
 bibtype = {article},
 author = {Dong, Yin Yao and Pike, Ashley C.W. and Mackenzie, Alexandra and McClenaghan, Conor and Aryal, Prafulla and Dong, Liang and Quigley, Andrew and Grieben, Mariana and Goubin, Solenne and Mukhopadhyay, Shubhashish and Ruda, Gian Filippo and Clausen, Michael V. and Cao, Lishuang and Brennan, Paul E. and Burgess-Brown, Nicola A. and Sansom, Mark S.P. and Tucker, Stephen J. and Carpenter, Elisabeth P.},
 doi = {10.1126/science.1261512},
 journal = {Science},
 number = {6227}
}

TREK-2 (KCNK10/K2P10), a two-pore domain potassium (K2P) channel, is gated by multiple stimuli such as stretch, fatty acids, and pH and by several drugs. However, the mechanisms that control channel gating are unclear. Here we present crystal structures of the human TREK-2 channel (up to 3.4 angstrom resolution) in two conformations and in complex with norfluoxetine, the active metabolite of fluoxetine (Prozac) and a state-dependent blocker of TREK channels. Norfluoxetine binds within intramembrane fenestrations found in only one of these two conformations. Channel activation by arachidonic acid and mechanical stretch involves conversion between these states through movement of the pore-lining helices. These results provide an explanation for TREK channel mechanosensitivity, regulation by diverse stimuli, and possible off-target effects of the serotonin reuptake inhibitor Prozac.

@article{
 title = {Betti reaction enables efficient synthesis of 8-hydroxyquinoline inhibitors of 2-oxoglutarate oxygenases},
 type = {article},
 year = {2015},
 keywords = {Dose-Response Relationship, Drug,Enzyme Inhibitors,Humans,Models, Molecular,Molecular Structure,Oxygenases,Oxyquinoline,Structure-Activity Relationship},
 pages = {15458-15461},
 volume = {51},
 month = {10},
 id = {e7c7f15e-5771-35ef-8f90-77b1e826cc93},
 created = {2016-12-01T10:12:01.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:49.660Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Thinnes2015},
 source_type = {JOUR},
 private_publication = {false},
 abstract = {<p>A Betti reaction was used for efficient generation of 2OG oxygenase inhibitors, including for KDM4 demethylases.</p>},
 bibtype = {article},
 author = {Thinnes, C. C. and Tumber, A. and Yapp, C. and Scozzafava, G. and Yeh, T. and Chan, M. C. and Tran, T. A. and Hsu, K. and Tarhonskaya, H. and Walport, L. J. and Wilkins, S. E. and Martinez, E. D. and Müller, S. and Pugh, C. W. and Ratcliffe, P. J. and Brennan, P. E. and Kawamura, A. and Schofield, C. J.},
 doi = {10.1039/c5cc06095h},
 journal = {Chemical Communications},
 number = {84}
}

A Betti reaction was used for efficient generation of 2OG oxygenase inhibitors, including for KDM4 demethylases.

@article{
 title = {Design and synthesis of potent and selective inhibitors of BRD7 and BRD9 bromodomains},
 type = {article},
 year = {2015},
 pages = {1381-1386},
 volume = {6},
 id = {3d7166fd-eb65-370b-bb8a-1f00ecd17fa1},
 created = {2017-11-28T02:10:04.400Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:46.250Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Hay2015},
 private_publication = {false},
 abstract = {<p>We describe potent and selective inhibitors of the BRD7 and BRD9 bromodomains intended for use as chemical probes to elucidate the biological roles of BRD7 and BRD9 in cells.</p>},
 bibtype = {article},
 author = {Hay, Duncan A. and Rogers, Catherine M. and Fedorov, Oleg and Tallant, Cynthia and Martin, Sarah and Monteiro, Octovia P. and Müller, Susanne and Knapp, Stefan and Schofield, Christopher J. and Brennan, Paul E.},
 doi = {10.1039/c5md00152h},
 journal = {MedChemComm},
 number = {7}
}

We describe potent and selective inhibitors of the BRD7 and BRD9 bromodomains intended for use as chemical probes to elucidate the biological roles of BRD7 and BRD9 in cells.

@article{
 title = {LP99: Discovery and synthesis of the first selective BRD7/9 bromodomain inhibitor},
 type = {article},
 year = {2015},
 keywords = {bromodomain,cascade reactions,enantioselective catalysis,epigenetics,organocatalysis},
 pages = {6217-6221},
 volume = {54},
 id = {29ce239b-9745-382d-b7d8-c256e172e864},
 created = {2017-11-28T02:10:04.460Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2019-01-21T14:39:22.121Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 citation_key = {Clark2015},
 private_publication = {false},
 abstract = {The bromodomain-containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin-remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone-fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure-based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity-building nitro-Mannich/lactamization cascade processes allowed for early structure-activity relationship studies whereas an enantioselective organocatalytic nitro-Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones in vitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro-inflammatory cytokine secretion.},
 bibtype = {article},
 author = {Clark, Peter G.K. and Vieira, Lucas C.C. and Tallant, Cynthia and Fedorov, Oleg and Singleton, Dean C. and Rogers, Catherine M. and Monteiro, Octovia P. and Bennett, James M. and Baronio, Roberta and Müller, Susanne and Daniels, Danette L. and Méndez, Jacqui and Knapp, Stefan and Brennan, Paul E. and Dixon, Darren J.},
 doi = {10.1002/anie.201501394},
 journal = {Angewandte Chemie - International Edition},
 number = {21}
}

The bromodomain-containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin-remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone-fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure-based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity-building nitro-Mannich/lactamization cascade processes allowed for early structure-activity relationship studies whereas an enantioselective organocatalytic nitro-Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones in vitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro-inflammatory cytokine secretion.

@article{
 title = {Optimisation of a triazolopyridine based histone demethylase inhibitor yields a potent and selective KDM2A (FBXL11) inhibitor},
 type = {article},
 year = {2014},
 pages = {1879-1886},
 volume = {5},
 websites = {http://dx.doi.org/10.1039/C4MD00291A,http://pubs.rsc.org/en/content/articlepdf/2014/md/c4md00291a},
 publisher = {The Royal Society of Chemistry},
 id = {d42854e0-accf-3fb1-a2e2-2d8ccbd34af4},
 created = {2015-10-01T17:18:05.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:45.992Z},
 read = {true},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {England2014},
 source_type = {Journal Article},
 private_publication = {false},
 abstract = {<p> Compound <bold>35</bold> is a potent and selective triazolopyridine inhibitor of the lysine demethylase KDM2A (pIC <sub>50</sub> 7.2). </p>},
 bibtype = {article},
 author = {England, Katherine S. and Tumber, Anthony and Krojer, Tobias and Scozzafava, Giuseppe and Ng, Stanley S. and Daniel, Michelle and Szykowska, Aleksandra and Che, Kahing and Von Delft, Frank and Burgess-Brown, Nicola A. and Kawamura, Akane and Schofield, Christopher J. and Brennan, Paul E.},
 doi = {10.1039/c4md00291a},
 journal = {MedChemComm},
 number = {12}
}

Compound 35 is a potent and selective triazolopyridine inhibitor of the lysine demethylase KDM2A (pIC ₅₀ 7.2).

@article{
 title = {Multiparameter optimization in CNS drug discovery: Design of pyrimido[4,5-d]azepines as potent 5-hydroxytryptamine 2C (5-HT2C) receptor agonists with exquisite functional selectivity over 5-HT2A and 5-HT2B receptors},
 type = {article},
 year = {2014},
 pages = {5258-5269},
 volume = {57},
 websites = {http://dx.doi.org/10.1021/jm5003292,http://pubs.acs.org/doi/pdfplus/10.1021/jm5003292},
 publisher = {American Chemical Society},
 id = {f65f3968-c2f8-3d4a-92a3-6f4e4f03e959},
 created = {2015-10-01T17:18:09.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:50.237Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Storer2014},
 source_type = {Journal Article},
 private_publication = {false},
 abstract = {A series of 4-substituted pyrimido[4,5-d]azepines that are potent, selective 5-HT2C receptor partial agonists is described. A rational medicinal chemistry design strategy to deliver CNS penetration coupled with SAR-based optimization of selectivity and agonist potency provided compounds with the desired balance of preclinical properties. Lead compounds 17 (PF-4479745) and 18 (PF-4522654) displayed robust pharmacology in a preclinical canine model of stress urinary incontinence (SUI) and no measurable functional agonism at the key selectivity targets 5-HT2A and 5-HT2B in relevant tissue-based assay systems. Utilizing recent advances in the structural biology of GPCRs, homology modeling has been carried out to rationalize binding and agonist efficacy of these compounds.},
 bibtype = {article},
 author = {Storer, R. Ian and Brennan, Paul E. and Brown, Alan D. and Bungay, Peter J. and Conlon, Kelly M. and Corbett, Matthew S. and Depianta, Robert P. and Fish, Paul V. and Heifetz, Alexander and Ho, Danny K H and Jessiman, Alan S. and McMurray, Gordon and De Oliveira, Cesar Augusto F and Roberts, Lee R. and Root, James A. and Shanmugasundaram, Veerabahu and Shapiro, Michael J. and Skerten, Melanie and Westbrook, Dominique and Wheeler, Simon and Whitlock, Gavin A. and Wright, John},
 doi = {10.1021/jm5003292},
 journal = {Journal of Medicinal Chemistry},
 number = {12}
}

A series of 4-substituted pyrimido[4,5-d]azepines that are potent, selective 5-HT2C receptor partial agonists is described. A rational medicinal chemistry design strategy to deliver CNS penetration coupled with SAR-based optimization of selectivity and agonist potency provided compounds with the desired balance of preclinical properties. Lead compounds 17 (PF-4479745) and 18 (PF-4522654) displayed robust pharmacology in a preclinical canine model of stress urinary incontinence (SUI) and no measurable functional agonism at the key selectivity targets 5-HT2A and 5-HT2B in relevant tissue-based assay systems. Utilizing recent advances in the structural biology of GPCRs, homology modeling has been carried out to rationalize binding and agonist efficacy of these compounds.

@article{
 title = {A series of potent crebbp bromodomain ligands reveals an induced-fit pocket stabilized by a cation-π interaction},
 type = {article},
 year = {2014},
 keywords = {CREBBP,bromodomain,enzyme inhibitors,epigenetics,ligand discovery},
 pages = {6126-6130},
 volume = {53},
 edition = {2014/05/14},
 id = {e611f068-c3bb-3a30-adf1-d94ffa529f8f},
 created = {2015-10-01T17:18:10.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:49.206Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Rooney2014a},
 source_type = {Journal Article},
 language = {eng},
 notes = {1521-3773<br/>Rooney, Timothy P C<br/>Filippakopoulos, Panagis<br/>Fedorov, Oleg<br/>Picaud, Sarah<br/>Cortopassi, Wilian A<br/>Hay, Duncan A<br/>Martin, Sarah<br/>Tumber, Anthony<br/>Rogers, Catherine M<br/>Philpott, Martin<br/>Wang, Minghua<br/>Thompson, Amber L<br/>Heightman, Tom D<br/>Pryde, David C<br/>Cook, Andrew<br/>Paton, Robert S<br/>Muller, Susanne<br/>Knapp, Stefan<br/>Brennan, Paul E<br/>Conway, Stuart J<br/>Journal Article<br/>Germany<br/>Angew Chem Int Ed Engl. 2014 Jun 10;53(24):6126-30. doi: 10.1002/anie.201402750. Epub 2014 May 12.},
 private_publication = {false},
 abstract = {The benzoxazinone and dihydroquinoxalinone fragments were employed as novel acetyl lysine mimics in the development of CREBBP bromodomain ligands. While the benzoxazinone series showed low affinity for the CREBBP bromodomain, expansion of the dihydroquinoxalinone series resulted in the first potent inhibitors of a bromodomain outside the BET family. Structural and computational studies reveal that an internal hydrogen bond stabilizes the protein-bound conformation of the dihydroquinoxalinone series. The side chain of this series binds in an induced-fit pocket forming a cation-π interaction with R1173 of CREBBP. The most potent compound inhibits binding of CREBBP to chromatin in U2OS cells.},
 bibtype = {article},
 author = {Rooney, Timothy P.C. and Filippakopoulos, Panagis and Fedorov, Oleg and Picaud, Sarah and Cortopassi, Wilian A. and Hay, Duncan A. and Martin, Sarah and Tumber, Anthony and Rogers, Catherine M. and Philpott, Martin and Wang, Minghua and Thompson, Amber L. and Heightman, Tom D. and Pryde, David C. and Cook, Andrew and Paton, Robert S. and Müller, Susanne and Knapp, Stefan and Brennan, Paul E. and Conway, Stuart J.},
 doi = {10.1002/anie.201402750},
 journal = {Angewandte Chemie - International Edition},
 number = {24}
}

The benzoxazinone and dihydroquinoxalinone fragments were employed as novel acetyl lysine mimics in the development of CREBBP bromodomain ligands. While the benzoxazinone series showed low affinity for the CREBBP bromodomain, expansion of the dihydroquinoxalinone series resulted in the first potent inhibitors of a bromodomain outside the BET family. Structural and computational studies reveal that an internal hydrogen bond stabilizes the protein-bound conformation of the dihydroquinoxalinone series. The side chain of this series binds in an induced-fit pocket forming a cation-π interaction with R1173 of CREBBP. The most potent compound inhibits binding of CREBBP to chromatin in U2OS cells.

@article{
 title = {[1,2,4]Triazolo[4,3-a]phthalazines: Inhibitors of diverse bromodomains},
 type = {article},
 year = {2014},
 pages = {462-476},
 volume = {57},
 websites = {http://pubs.acs.org/doi/abs/10.1021/jm401568s,http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906316/pdf/jm401568s.pdf},
 publisher = {American Chemical Society},
 id = {0762735f-ae86-3d41-8ce3-b731c3207480},
 created = {2015-10-01T17:18:12.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:45.796Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Fedorov2014},
 source_type = {Journal Article},
 private_publication = {false},
 abstract = {Bromodomains are gaining increasing interest as drug targets. Commercially sourced and de novo synthesized substituted [1,2,4]triazolo[4,3-a]phthalazines are potent inhibitors of both the BET bromodomains such as BRD4 as well as bromodomains outside the BET family such as BRD9,CECR2,and CREBBP.Thisnew series of compounds is the first example of submicromolar inhibitors of bromodomains outside the BET subfamily. Representative compounds are active in cells exhibiting potent cellular inhibition activity in a FRAP model of CREBBP and chromatin association. The compounds described are valuable starting points for discovery of selective bromodomain inhibitors and inhibitors with mixed bromodomain pharmacology.},
 bibtype = {article},
 author = {Fedorov, Oleg and Lingard, Hannah and Wells, Chris and Monteiro, Octovia P. and Picaud, Sarah and Keates, Tracy and Yapp, Clarence and Philpott, Martin and Martin, Sarah J. and Felletar, Ildiko and Marsden, Brian D. and Filippakopoulos, Panagis and Müller, Susanne and Knapp, Stefan and Brennan, Paul E.},
 doi = {10.1021/jm401568s},
 journal = {Journal of Medicinal Chemistry},
 number = {2}
}

Bromodomains are gaining increasing interest as drug targets. Commercially sourced and de novo synthesized substituted [1,2,4]triazolo[4,3-a]phthalazines are potent inhibitors of both the BET bromodomains such as BRD4 as well as bromodomains outside the BET family such as BRD9,CECR2,and CREBBP.Thisnew series of compounds is the first example of submicromolar inhibitors of bromodomains outside the BET subfamily. Representative compounds are active in cells exhibiting potent cellular inhibition activity in a FRAP model of CREBBP and chromatin association. The compounds described are valuable starting points for discovery of selective bromodomain inhibitors and inhibitors with mixed bromodomain pharmacology.

@article{
 title = {Machine-assisted synthesis of modulators of the histone reader BRD9 using flow methods of chemistry and frontal affinity chromatography},
 type = {article},
 year = {2014},
 pages = {540-546},
 volume = {5},
 websites = {http://dx.doi.org/10.1039/C4MD00007B},
 publisher = {The Royal Society of Chemistry},
 id = {da4bf2dd-1810-37a4-9bf3-308404f619c2},
 created = {2015-10-01T17:18:15.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:50.411Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Guetzoyan2014},
 source_type = {Journal Article},
 private_publication = {false},
 abstract = {<p>Novel technologies were developed and used for the synthesis and evaluation of new triazolopyridazine BRD9 inhibitors.</p>},
 bibtype = {article},
 author = {Guetzoyan, Lucie and Ingham, Richard J. and Nikbin, Nikzad and Rossignol, Julien and Wolling, Michael and Baumert, Mark and Burgess-Brown, Nicola A. and Strain-Damerell, Claire M. and Shrestha, Leela and Brennan, Paul E. and Fedorov, Oleg and Knapp, Stefan and Ley, Steven V.},
 doi = {10.1039/c4md00007b},
 journal = {MedChemComm},
 number = {4}
}

Novel technologies were developed and used for the synthesis and evaluation of new triazolopyridazine BRD9 inhibitors.

@article{
 title = {Discovery and optimization of small-molecule ligands for the CBP/p300 bromodomains},
 type = {article},
 year = {2014},
 pages = {9308-9319},
 volume = {136},
 websites = {http://pubs.acs.org/doi/abs/10.1021/ja412434f,http://pubs.acs.org/doi/pdfplus/10.1021/ja412434f},
 publisher = {American Chemical Society},
 id = {51501af5-11dd-3531-a962-a935a4e31ebd},
 created = {2015-10-07T14:20:50.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:46.224Z},
 read = {true},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Hay2014},
 source_type = {Journal Article},
 private_publication = {false},
 abstract = {Small-molecule inhibitors that target bromodomains outside of the bromodomain and extra-terminal (BET) sub-family are lacking. Here, we describe highly potent and selective ligands for the bromodomain module of the human lysine acetyl transferase CBP/p300, developed from a series of 5-isoxazolyl-benzimidazoles. Our starting point was a fragment hit, which was optimized into a more potent and selective lead using parallel synthesis employing Suzuki couplings, benzimidazole-forming reactions, and reductive aminations. The selectivity of the lead compound against other bromodomain family members was investigated using a thermal stability assay, which revealed some inhibition of the structurally related BET family members. To address the BET selectivity issue, X-ray crystal structures of the lead compound bound to the CREB binding protein (CBP) and the first bromodomain of BRD4 (BRD4(1)) were used to guide the design of more selective compounds. The crystal structures obtained revealed two distinct binding modes. By varying the aryl substitution pattern and developing conformationally constrained analogues, selectivity for CBP over BRD4(1) was increased. The optimized compound is highly potent (Kd = 21 nM) and selective, displaying 40-fold selectivity over BRD4(1). Cellular activity was demonstrated using fluorescence recovery after photo-bleaching (FRAP) and a p53 reporter assay. The optimized compounds are cell-active and have nanomolar affinity for CBP/p300; therefore, they should be useful in studies investigating the biological roles of CBP and p300 and to validate the CBP and p300 bromodomains as therapeutic targets.},
 bibtype = {article},
 author = {Hay, Duncan A. and Fedorov, Oleg and Martin, Sarah and Singleton, Dean C. and Tallant, Cynthia and Wells, Christopher and Picaud, Sarah and Philpott, Martin and Monteiro, Octovia P. and Rogers, Catherine M. and Conway, Stuart J. and Rooney, Timothy P.C. and Tumber, Anthony and Yapp, Clarence and Filippakopoulos, Panagis and Bunnage, Mark E. and Müller, Susanne and Knapp, Stefan and Schofield, Christopher J. and Brennan, Paul E.},
 doi = {10.1021/ja412434f},
 journal = {Journal of the American Chemical Society},
 number = {26}
}

Small-molecule inhibitors that target bromodomains outside of the bromodomain and extra-terminal (BET) sub-family are lacking. Here, we describe highly potent and selective ligands for the bromodomain module of the human lysine acetyl transferase CBP/p300, developed from a series of 5-isoxazolyl-benzimidazoles. Our starting point was a fragment hit, which was optimized into a more potent and selective lead using parallel synthesis employing Suzuki couplings, benzimidazole-forming reactions, and reductive aminations. The selectivity of the lead compound against other bromodomain family members was investigated using a thermal stability assay, which revealed some inhibition of the structurally related BET family members. To address the BET selectivity issue, X-ray crystal structures of the lead compound bound to the CREB binding protein (CBP) and the first bromodomain of BRD4 (BRD4(1)) were used to guide the design of more selective compounds. The crystal structures obtained revealed two distinct binding modes. By varying the aryl substitution pattern and developing conformationally constrained analogues, selectivity for CBP over BRD4(1) was increased. The optimized compound is highly potent (Kd = 21 nM) and selective, displaying 40-fold selectivity over BRD4(1). Cellular activity was demonstrated using fluorescence recovery after photo-bleaching (FRAP) and a p53 reporter assay. The optimized compounds are cell-active and have nanomolar affinity for CBP/p300; therefore, they should be useful in studies investigating the biological roles of CBP and p300 and to validate the CBP and p300 bromodomains as therapeutic targets.

@inproceedings{
 title = {Optimizing in vivo probes for the BET bromodomains},
 type = {inproceedings},
 year = {2014},
 volume = {248},
 websites = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000349167402158&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=4fd6f7d59a501f9b8bac2be37914c43e},
 month = {8},
 day = {10},
 id = {eb2b3663-f88c-3068-a009-11ec30364719},
 created = {2016-12-01T10:12:02.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:49.775Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Jennings2014},
 source_type = {CONF},
 private_publication = {false},
 bibtype = {inproceedings},
 author = {Jennings, L E and Hewings, D S and Humphreys, P G and Brennan, P E and Conway, S J},
 booktitle = {Abstracts of Papers of the American Chemical Society}
}

@article{
 title = {5-Carboxy-8-hydroxyquinoline is a broad spectrum 2-oxoglutarate oxygenase inhibitor which causes iron translocation},
 type = {article},
 year = {2013},
 pages = {3110-3117},
 volume = {4},
 websites = {http://dx.doi.org/10.1039/C3SC51122G,http://pubs.rsc.org/en/content/articlepdf/2013/sc/c3sc51122g},
 publisher = {The Royal Society of Chemistry},
 id = {20748034-ac8d-3c5a-bbd8-0e7821937694},
 created = {2015-10-01T17:17:55.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:48.888Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Hopkinson2013},
 source_type = {Journal Article},
 private_publication = {false},
 abstract = {2-Oxoglutarate and iron dependent oxygenases are therapeutic targets for human diseases. Using a representative 2OG oxygenase panel, we compare the inhibitory activities of 5-carboxy-8-hydroxyquinoline (IOX1) and 4-carboxy-8-hydroxyquinoline (4C8HQ) with that of two other commonly used 2OG oxygenase inhibitors, N-oxalylglycine (NOG) and 2,4-pyridinedicarboxylic acid (2,4-PDCA). The results reveal that IOX1 has a broad spectrum of activity, as demonstrated by the inhibition of transcription factor hydroxylases, representatives of all 2OG dependent histone demethylase subfamilies, nucleic acid demethylases and γ-butyrobetaine hydroxylase. Cellular assays show that, unlike NOG and 2,4-PDCA, IOX1 is active against both cytosolic and nuclear 2OG oxygenases without ester derivatisation. Unexpectedly, crystallographic studies on these oxygenases demonstrate that IOX1, but not 4C8HQ, can cause translocation of the active site metal, revealing a rare example of protein ligand-induced metal movement.},
 bibtype = {article},
 author = {Hopkinson, Richard J. and Tumber, Anthony and Yapp, Clarence and Chowdhury, Rasheduzzaman and Aik, Wei Shen and Che, Ka Hing and Li, Xuan Shirley and Kristensen, Jan B.L. and King, Oliver N.F. and Chan, Mun Chiang and Yeoh, Kar Kheng and Choi, Hwanho and Walport, Louise J. and Thinnes, Cyrille C. and Bush, Jacob T. and Lejeune, Clarisse and Rydzik, Anna M. and Rose, Nathan R. and Bagg, Eleanor A. and McDonough, Michael A. and Krojer, Tobias J. and Yue, Wyatt W. and Ng, Stanley S. and Olsen, Lars and Brennan, Paul E. and Oppermann, Udo and Müller, Susanne and Klose, Robert J. and Ratcliffe, Peter J. and Schofield, Christopher J. and Kawamura, Akane},
 doi = {10.1039/c3sc51122g},
 journal = {Chemical Science},
 number = {8}
}

2-Oxoglutarate and iron dependent oxygenases are therapeutic targets for human diseases. Using a representative 2OG oxygenase panel, we compare the inhibitory activities of 5-carboxy-8-hydroxyquinoline (IOX1) and 4-carboxy-8-hydroxyquinoline (4C8HQ) with that of two other commonly used 2OG oxygenase inhibitors, N-oxalylglycine (NOG) and 2,4-pyridinedicarboxylic acid (2,4-PDCA). The results reveal that IOX1 has a broad spectrum of activity, as demonstrated by the inhibition of transcription factor hydroxylases, representatives of all 2OG dependent histone demethylase subfamilies, nucleic acid demethylases and γ-butyrobetaine hydroxylase. Cellular assays show that, unlike NOG and 2,4-PDCA, IOX1 is active against both cytosolic and nuclear 2OG oxygenases without ester derivatisation. Unexpectedly, crystallographic studies on these oxygenases demonstrate that IOX1, but not 4C8HQ, can cause translocation of the active site metal, revealing a rare example of protein ligand-induced metal movement.

@article{
 title = {PFI-1, a highly selective protein interaction inhibitor, targeting BET bromodomains},
 type = {article},
 year = {2013},
 pages = {3336-3346},
 volume = {73},
 websites = {http://cancerres.aacrjournals.org/content/73/11/3336.abstract,http://cancerres.aacrjournals.org/content/73/11/3336.full.pdf},
 id = {cc406dfe-29b5-3e48-b885-a4fae2c40a90},
 created = {2015-10-01T17:17:59.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:49.733Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Picaud2013a},
 source_type = {Journal Article},
 private_publication = {false},
 abstract = {Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT) are transcriptional regulators required for efficient expression of several growth promoting and antiapoptotic genes as well as for cell-cycle progression. BET proteins are recruited on transcriptionally active chromatin via their two N-terminal bromodomains (BRD), a protein interaction module that specifically recognizes acetylated lysine residues in histones H3 and H4. Inhibition of the BET-histone interaction results in transcriptional downregulation of a number of oncogenes, providing a novel pharmacologic strategy for the treatment of cancer. Here, we present a potent and highly selective dihydroquinazoline-2-one inhibitor, PFI-1, which efficiently blocks the interaction of BET BRDs with acetylated histone tails. Cocrystal structures showed that PFI-1 acts as an acetyl-lysine (Kac) mimetic inhibitor efficiently occupying the Kac binding site in BRD4 and BRD2. PFI-1 has antiproliferative effects on leukemic cell lines and efficiently abrogates their clonogenic growth. Exposure of sensitive cell lines with PFI-1 results in G1 cell-cycle arrest, downregulation of MYC expression, as well as induction of apoptosis and induces differentiation of primary leukemic blasts. Intriguingly, cells exposed to PFI-1 showed significant downregulation of Aurora B kinase, thus attenuating phosphorylation of the Aurora substrate H3S10, providing an alternative strategy for the specific inhibition of this well-established oncology target.},
 bibtype = {article},
 author = {Picaud, Sarah and Da Costa, David and Thanasopoulou, Angeliki and Filippakopoulos, Panagis and Fish, Paul V. and Philpott, Martin and Fedorov, Oleg and Brennan, Paul and Bunnage, Mark E. and Owen, Dafydd R. and Bradner, James E. and Taniere, Philippe and O'Sullivan, Brendan and Müller, Susanne and Schwaller, Juerg and Stankovic, Tatjana and Knapp, Stefan},
 doi = {10.1158/0008-5472.CAN-12-3292},
 journal = {Cancer Research},
 number = {11}
}

Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT) are transcriptional regulators required for efficient expression of several growth promoting and antiapoptotic genes as well as for cell-cycle progression. BET proteins are recruited on transcriptionally active chromatin via their two N-terminal bromodomains (BRD), a protein interaction module that specifically recognizes acetylated lysine residues in histones H3 and H4. Inhibition of the BET-histone interaction results in transcriptional downregulation of a number of oncogenes, providing a novel pharmacologic strategy for the treatment of cancer. Here, we present a potent and highly selective dihydroquinazoline-2-one inhibitor, PFI-1, which efficiently blocks the interaction of BET BRDs with acetylated histone tails. Cocrystal structures showed that PFI-1 acts as an acetyl-lysine (Kac) mimetic inhibitor efficiently occupying the Kac binding site in BRD4 and BRD2. PFI-1 has antiproliferative effects on leukemic cell lines and efficiently abrogates their clonogenic growth. Exposure of sensitive cell lines with PFI-1 results in G1 cell-cycle arrest, downregulation of MYC expression, as well as induction of apoptosis and induces differentiation of primary leukemic blasts. Intriguingly, cells exposed to PFI-1 showed significant downregulation of Aurora B kinase, thus attenuating phosphorylation of the Aurora substrate H3S10, providing an alternative strategy for the specific inhibition of this well-established oncology target.

@article{
 title = {RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain},
 type = {article},
 year = {2013},
 pages = {19754-19759},
 volume = {110},
 websites = {http://www.pnas.org/cgi/doi/10.1073/pnas.1310658110},
 id = {de87f4ff-10cd-37ab-bc46-c82d5422ca88},
 created = {2015-10-01T17:17:59.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:49.776Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Picaud2013c},
 source_type = {Journal Article},
 private_publication = {false},
 abstract = {Bromodomains have emerged as attractive candidates for the development of inhibitors targeting gene transcription. Inhibitors of the bromo and extraterminal (BET) family recently showed promising activity in diverse disease models. However, the pleiotropic nature of BET proteins regulating tissue-specific transcription has raised safety concerns and suggested that attempts should be made for domain-specific targeting. Here, we report that RVX-208, a compound currently in phase II clinical trials, is a BET bromodomain inhibitor specific for second bromodomains (BD2s). Cocrystal structures revealed binding modes of RVX-208 and its synthetic precursor, and fluorescent recovery after photobleaching demonstrated that RVX-208 displaces BET proteins from chromatin. However, gene-expression data showed that BD2 inhibition only modestly affects BET-dependent gene transcription. Our data demonstrate the feasibility of specific targeting within the BET family resulting in different transcriptional outcomes and highlight the importance of BD1 in transcriptional regulation.},
 bibtype = {article},
 author = {Picaud, S. and Wells, C. and Felletar, I. and Brotherton, D. and Martin, S. and Savitsky, P. and Diez-Dacal, B. and Philpott, M. and Bountra, C. and Lingard, H. and Fedorov, O. and Muller, S. and Brennan, P. E. and Knapp, S. and Filippakopoulos, P.},
 doi = {10.1073/pnas.1310658110},
 journal = {Proceedings of the National Academy of Sciences},
 number = {49}
}

Bromodomains have emerged as attractive candidates for the development of inhibitors targeting gene transcription. Inhibitors of the bromo and extraterminal (BET) family recently showed promising activity in diverse disease models. However, the pleiotropic nature of BET proteins regulating tissue-specific transcription has raised safety concerns and suggested that attempts should be made for domain-specific targeting. Here, we report that RVX-208, a compound currently in phase II clinical trials, is a BET bromodomain inhibitor specific for second bromodomains (BD2s). Cocrystal structures revealed binding modes of RVX-208 and its synthetic precursor, and fluorescent recovery after photobleaching demonstrated that RVX-208 displaces BET proteins from chromatin. However, gene-expression data showed that BD2 inhibition only modestly affects BET-dependent gene transcription. Our data demonstrate the feasibility of specific targeting within the BET family resulting in different transcriptional outcomes and highlight the importance of BD1 in transcriptional regulation.

@article{
 title = {Fragment-based hit identification: thinking in 3D.},
 type = {article},
 year = {2013},
 pages = {1221-7},
 volume = {18},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/23906694},
 id = {5736eab5-af75-3282-b0b9-af7a2104948c},
 created = {2015-10-01T17:18:05.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:50.808Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Morley2013},
 source_type = {Journal Article},
 private_publication = {false},
 abstract = {The identification of high-quality hits during the early phases of drug discovery is essential if projects are to have a realistic chance of progressing into clinical development and delivering marketed drugs. As the pharmaceutical industry goes through unprecedented change, there are increasing opportunities to collaborate via pre-competitive networks to marshal multifunctional resources and knowledge to drive impactful, innovative science. The 3D Fragment Consortium is developing fragment-screening libraries with enhanced 3D characteristics and evaluating their effect on the quality of fragment-based hit identification (FBHI) projects.},
 bibtype = {article},
 author = {Morley, Andrew D. and Pugliese, Angelo and Birchall, Kristian and Bower, Justin and Brennan, Paul and Brown, Nathan and Chapman, Tim and Drysdale, Martin and Gilbert, Ian H. and Hoelder, Swen and Jordan, Allan and Ley, Steven V. and Merritt, Andy and Miller, David and Swarbrick, Martin E. and Wyatt, Paul G.},
 doi = {10.1016/j.drudis.2013.07.011},
 journal = {Drug discovery today},
 number = {23-24}
}

The identification of high-quality hits during the early phases of drug discovery is essential if projects are to have a realistic chance of progressing into clinical development and delivering marketed drugs. As the pharmaceutical industry goes through unprecedented change, there are increasing opportunities to collaborate via pre-competitive networks to marshal multifunctional resources and knowledge to drive impactful, innovative science. The 3D Fragment Consortium is developing fragment-screening libraries with enhanced 3D characteristics and evaluating their effect on the quality of fragment-based hit identification (FBHI) projects.

@article{
 title = {Optimization of 3,5-dimethylisoxazole derivatives as potent bromodomain ligands},
 type = {article},
 year = {2013},
 keywords = {Acetylation,CREB-Binding Protein,CREB-Binding Protein: metabolism,Cell Line,Crystallography,Histones,Histones: metabolism,Humans,Inhibitory Concentration 50,Isoxazoles,Isoxazoles: chemical synthesis,Isoxazoles: chemistry,Isoxazoles: pharmacology,Ligands,Lysine,Lysine: metabolism,Nuclear Proteins,Nuclear Proteins: antagonists & inhibitors,Nuclear Proteins: chemistry,Protein Binding,Structure-Activity Relationship,Transcription Factors,Transcription Factors: antagonists & inhibitors,Transcription Factors: chemistry,Tumor,X-Ray},
 pages = {3217-3227},
 volume = {56},
 websites = {http://dx.doi.org/10.1021/jm301588r,http://pubs.acs.org/doi/pdfplus/10.1021/jm301588r},
 publisher = {American Chemical Society},
 id = {57c47b0b-cadc-37ad-be67-b48262975e18},
 created = {2015-10-07T14:20:50.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:48.802Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Hewings2013},
 source_type = {Journal Article},
 private_publication = {false},
 abstract = {The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors of the BET (bromodomain and extra terminal domain) bromodomain family with good ligand efficiency. X-ray crystal structures of the most potent compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that the phenol and acetate derivatives of the lead compounds showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas the reported compounds showed no general cytotoxicity in other cancer cell lines tested.},
 bibtype = {article},
 author = {Hewings, David S. and Fedorov, Oleg and Filippakopoulos, Panagis and Martin, Sarah and Picaud, Sarah and Tumber, Anthony and Wells, Christopher and Olcina, Monica M. and Freeman, Katherine and Gill, Andrew and Ritchie, Alison J. and Sheppard, David W. and Russell, Angela J. and Hammond, Ester M. and Knapp, Stefan and Brennan, Paul E. and Conway, Stuart J.},
 doi = {10.1021/jm301588r},
 journal = {Journal of Medicinal Chemistry},
 number = {8}
}

The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors of the BET (bromodomain and extra terminal domain) bromodomain family with good ligand efficiency. X-ray crystal structures of the most potent compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that the phenol and acetate derivatives of the lead compounds showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas the reported compounds showed no general cytotoxicity in other cancer cell lines tested.

@article{
 title = {The design and synthesis of 5- and 6-isoxazolylbenzimidazoles as selective inhibitors of the BET bromodomains},
 type = {article},
 year = {2013},
 pages = {140-144},
 volume = {4},
 websites = {http://dx.doi.org/10.1039/C2MD20189E},
 publisher = {The Royal Society of Chemistry},
 id = {a47b4983-980f-3296-b401-6629390c41da},
 created = {2015-10-07T14:20:50.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:46.113Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Hay2013},
 source_type = {Journal Article},
 private_publication = {false},
 abstract = {Simple 1-substituted 5- and 6-isoxazolyl-benzimidazoles have been shown to be potent inhibitors of the BET bromodomains with selectivity over the related bromodomain of CBP. The reported inhibitors were prepared from simple starting materials in two steps followed by separation of the regioisomers or regioselectively in three steps},
 bibtype = {article},
 author = {Hay, Duncan and Fedorov, Oleg and Filippakopoulos, Panagis and Martin, Sarah and Philpott, Martin and Picaud, Sarah and Hewings, David S. and Uttakar, Sagar and Heightman, Tom D. and Conway, Stuart J. and Knapp, Stefan and Brennan, Paul E.},
 doi = {10.1039/c2md20189e},
 journal = {MedChemComm},
 number = {1}
}

Simple 1-substituted 5- and 6-isoxazolyl-benzimidazoles have been shown to be potent inhibitors of the BET bromodomains with selectivity over the related bromodomain of CBP. The reported inhibitors were prepared from simple starting materials in two steps followed by separation of the regioisomers or regioselectively in three steps

@inproceedings{
 title = {Chemical probes for bromodomains outside the BET family},
 type = {inproceedings},
 year = {2013},
 volume = {246},
 websites = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000329618404684&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=4fd6f7d59a501f9b8bac2be37914c43e},
 month = {9},
 day = {8},
 id = {875eb53a-53e1-33fa-85bc-06a0f1284962},
 created = {2016-12-01T10:12:01.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:50.239Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Brennan2013},
 source_type = {CONF},
 private_publication = {false},
 bibtype = {inproceedings},
 author = {Brennan, P E and Martin, S J and Monteiro, O and Fedorov, O and Knapp, S and Hay, D and Wells, C and Filippakopoulos, P and Picaud, S and Muller-Knapp, S and Keates, T and Yapp, C and Philpott, M and Schofield, C and Burgess-Brown, N and Shrestha, L and Strain-Damerell, C},
 booktitle = {Abstracts of Papers of the American Chemical Society}
}

@article{
 title = {PFI-1, a highly selective protein interaction inhibitor, targeting BET bromodomains},
 type = {article},
 year = {2013},
 pages = {3336-3346},
 volume = {73},
 id = {f245d96d-6365-3122-9fae-9d8175f97d4e},
 created = {2017-11-28T02:10:04.525Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:49.916Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Picaud2013b},
 private_publication = {false},
 abstract = {Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT) are transcriptional regulators required for efficient expression of several growth promoting and antiapoptotic genes as well as for cell-cycle progression. BET proteins are recruited on transcriptionally active chromatin via their two N-terminal bromodomains (BRD), a protein interaction module that specifically recognizes acetylated lysine residues in histones H3 and H4. Inhibition of the BET-histone interaction results in transcriptional downregulation of a number of oncogenes, providing a novel pharmacologic strategy for the treatment of cancer. Here, we present a potent and highly selective dihydroquinazoline-2-one inhibitor, PFI-1, which efficiently blocks the interaction of BET BRDs with acetylated histone tails. Cocrystal structures showed that PFI-1 acts as an acetyl-lysine (Kac) mimetic inhibitor efficiently occupying the Kac binding site in BRD4 and BRD2. PFI-1 has antiproliferative effects on leukemic cell lines and efficiently abrogates their clonogenic growth. Exposure of sensitive cell lines with PFI-1 results in G1 cell-cycle arrest, downregulation of MYC expression, as well as induction of apoptosis and induces differentiation of primary leukemic blasts. Intriguingly, cells exposed to PFI-1 showed significant downregulation of Aurora B kinase, thus attenuating phosphorylation of the Aurora substrate H3S10, providing an alternative strategy for the specific inhibition of this well-established oncology target.},
 bibtype = {article},
 author = {Picaud, Sarah and Da Costa, David and Thanasopoulou, Angeliki and Filippakopoulos, Panagis and Fish, Paul V. and Philpott, Martin and Fedorov, Oleg and Brennan, Paul and Bunnage, Mark E. and Owen, Dafydd R. and Bradner, James E. and Taniere, Philippe and O'Sullivan, Brendan and Müller, Susanne and Schwaller, Juerg and Stankovic, Tatjana and Knapp, Stefan},
 doi = {10.1158/0008-5472.CAN-12-3292},
 journal = {Cancer Research},
 number = {11}
}

Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT) are transcriptional regulators required for efficient expression of several growth promoting and antiapoptotic genes as well as for cell-cycle progression. BET proteins are recruited on transcriptionally active chromatin via their two N-terminal bromodomains (BRD), a protein interaction module that specifically recognizes acetylated lysine residues in histones H3 and H4. Inhibition of the BET-histone interaction results in transcriptional downregulation of a number of oncogenes, providing a novel pharmacologic strategy for the treatment of cancer. Here, we present a potent and highly selective dihydroquinazoline-2-one inhibitor, PFI-1, which efficiently blocks the interaction of BET BRDs with acetylated histone tails. Cocrystal structures showed that PFI-1 acts as an acetyl-lysine (Kac) mimetic inhibitor efficiently occupying the Kac binding site in BRD4 and BRD2. PFI-1 has antiproliferative effects on leukemic cell lines and efficiently abrogates their clonogenic growth. Exposure of sensitive cell lines with PFI-1 results in G1 cell-cycle arrest, downregulation of MYC expression, as well as induction of apoptosis and induces differentiation of primary leukemic blasts. Intriguingly, cells exposed to PFI-1 showed significant downregulation of Aurora B kinase, thus attenuating phosphorylation of the Aurora substrate H3S10, providing an alternative strategy for the specific inhibition of this well-established oncology target.

@article{
 title = {Progress in the Development and Application of Small Molecule Inhibitors of Bromodomain–Acetyl-lysine Interactions},
 type = {article},
 year = {2012},
 pages = {9393-9413},
 volume = {55},
 websites = {http://pubs.acs.org/doi/10.1021/jm300915b},
 publisher = {American Chemical Society},
 id = {47bf5fc5-5933-3417-aba9-7bacb63eba37},
 created = {2015-10-01T17:17:59.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:46.364Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Hewings2012b},
 source_type = {Journal Article},
 private_publication = {false},
 abstract = {Bromodomains, protein modules that recognize and bind to acetylated lysine, are emerging as important components of cellular machinery. These acetyl-lysine (KAc) “reader” domains are part of the write–read–erase concept that has been linked with the transfer of epigenetic information. By reading KAc marks on histones, bromodomains mediate protein–protein interactions between a diverse array of partners. There has been intense activity in developing potent and selective small molecule probes that disrupt the interaction between a given bromodomain and KAc. Rapid success has been achieved with the BET family of bromodomains, and a number of potent and selective probes have been reported. These compounds have enabled linking of the BET bromodomains with diseases, including cancer and inflammation, suggesting that bromodomains are druggable targets. Herein, we review the biology of the bromodomains and discuss the SAR for the existing small molecule probes. The biology that has been enabled by these compounds...},
 bibtype = {article},
 author = {Hewings, David S. and Rooney, Timothy P. C. and Jennings, Laura E. and Hay, Duncan A. and Schofield, Christopher J. and Brennan, Paul E. and Knapp, Stefan and Conway, Stuart J.},
 doi = {10.1021/jm300915b},
 journal = {Journal of Medicinal Chemistry},
 number = {22}
}

Bromodomains, protein modules that recognize and bind to acetylated lysine, are emerging as important components of cellular machinery. These acetyl-lysine (KAc) “reader” domains are part of the write–read–erase concept that has been linked with the transfer of epigenetic information. By reading KAc marks on histones, bromodomains mediate protein–protein interactions between a diverse array of partners. There has been intense activity in developing potent and selective small molecule probes that disrupt the interaction between a given bromodomain and KAc. Rapid success has been achieved with the BET family of bromodomains, and a number of potent and selective probes have been reported. These compounds have enabled linking of the BET bromodomains with diseases, including cancer and inflammation, suggesting that bromodomains are druggable targets. Herein, we review the biology of the bromodomains and discuss the SAR for the existing small molecule probes. The biology that has been enabled by these compounds...

@article{
 title = {The therapeutic potential of acetyl-lysine and methyl-lysine effector domains},
 type = {article},
 year = {2012},
 pages = {e101-e110},
 volume = {9},
 websites = {http://www.sciencedirect.com/science/article/pii/S1740677312000125},
 id = {cd8e49d9-4a42-33f5-891d-ccae05fb0fbb},
 created = {2015-10-01T17:17:59.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:46.398Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Brennan2012a},
 source_type = {Journal Article},
 private_publication = {false},
 abstract = {Epigenetic reader domains are protein interaction modules that selectively recognize common post-translational modification on histones and other nuclear proteins such as ε-N-acetylated lysine or methyllysine/arginine residues. Interactions mediated by these effector domains result in the recruitment of gene specific transcriptional regulators. This review focusses on reader domains that recognize acetylated and methylated lysine and arginine residues. Bromodomains selectively recognize acetylated lysines residues and inhibitors have recently emerged as promising lead compounds for the treatment of cancer and inflammatory diseases, acting by specifically repressing expression of oncogenes and pro-inflammatory cytokines. Initial inhibitors have also been reported for methyllysine binding domains. Here we review recent development of this emerging target area. © 2012 Elsevier Ltd. All rights reserved.},
 bibtype = {article},
 author = {Brennan, Paul and Filippakopoulos, Panagis and Knapp, Stefan},
 doi = {10.1016/j.ddstr.2012.04.001},
 journal = {Drug Discovery Today: Therapeutic Strategies},
 number = {2-3}
}

Epigenetic reader domains are protein interaction modules that selectively recognize common post-translational modification on histones and other nuclear proteins such as ε-N-acetylated lysine or methyllysine/arginine residues. Interactions mediated by these effector domains result in the recruitment of gene specific transcriptional regulators. This review focusses on reader domains that recognize acetylated and methylated lysine and arginine residues. Bromodomains selectively recognize acetylated lysines residues and inhibitors have recently emerged as promising lead compounds for the treatment of cancer and inflammatory diseases, acting by specifically repressing expression of oncogenes and pro-inflammatory cytokines. Initial inhibitors have also been reported for methyllysine binding domains. Here we review recent development of this emerging target area. © 2012 Elsevier Ltd. All rights reserved.

@article{
 title = {Plant growth regulator daminozide is a selective inhibitor of human KDM2/7 histone demethylases},
 type = {article},
 year = {2012},
 pages = {6639-6643},
 volume = {55},
 websites = {http://dx.doi.org/10.1021/jm300677j},
 publisher = {American Chemical Society},
 id = {d4e1d094-2211-397b-91c5-34fc48ac9855},
 created = {2015-10-01T17:18:01.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:45.878Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Rose2012},
 source_type = {Journal Article},
 private_publication = {false},
 abstract = {The JmjC oxygenases catalyze the N-demethylation of N(ε)-methyl lysine residues in histones and are current therapeutic targets. A set of human 2-oxoglutarate analogues were screened using a unified assay platform for JmjC demethylases and related oxygenases. Results led to the finding that daminozide (N-(dimethylamino)succinamic acid, 160 Da), a plant growth regulator, selectively inhibits the KDM2/7 JmjC subfamily. Kinetic and crystallographic studies reveal that daminozide chelates the active site metal via its hydrazide carbonyl and dimethylamino groups.},
 bibtype = {article},
 author = {Rose, Nathan R. and Woon, Esther C Y and Tumber, Anthony and Walport, Louise J. and Chowdhury, Rasheduzzaman and Li, Xuan Shirley and King, Oliver N F and Lejeune, Clarisse and Ng, Stanley S. and Krojer, Tobias and Chan, Mun Chiang and Rydzik, Anna M. and Hopkinson, Richard J. and Che, Ka Hing and Daniel, Michelle and Strain-Damerell, Claire and Gileadi, Carina and Kochan, Grazyna and Leung, Ivanhoe K H and Dunford, James and Yeoh, Kar Kheng and Ratcliffe, Peter J. and Burgess-Brown, Nicola and Von Delft, Frank and Muller, Susanne and Marsden, Brian and Brennan, Paul E. and McDonough, Michael A. and Oppermann, Udo and Klose, Robert J. and Schofield, Christopher J. and Kawamura, Akane},
 doi = {10.1021/jm300677j},
 journal = {Journal of Medicinal Chemistry},
 number = {14}
}

The JmjC oxygenases catalyze the N-demethylation of N(ε)-methyl lysine residues in histones and are current therapeutic targets. A set of human 2-oxoglutarate analogues were screened using a unified assay platform for JmjC demethylases and related oxygenases. Results led to the finding that daminozide (N-(dimethylamino)succinamic acid, 160 Da), a plant growth regulator, selectively inhibits the KDM2/7 JmjC subfamily. Kinetic and crystallographic studies reveal that daminozide chelates the active site metal via its hydrazide carbonyl and dimethylamino groups.

@article{
 title = {Identification of a chemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of a fragment-derived hit},
 type = {article},
 year = {2012},
 keywords = {Crystallography,Humans,Models,Molecular,Molecular Probes,Molecular Probes: chemical synthesis,Molecular Probes: pharmacology,Molecular Structure,Nuclear Proteins,Nuclear Proteins: antagonists & inhibitors,Nuclear Proteins: metabolism,Protein Binding,Quinazolinones,Quinazolinones: chemical synthesis,Quinazolinones: pharmacology,Structure-Activity Relationship,Sulfonamides,Sulfonamides: chemical synthesis,Sulfonamides: chemistry,Sulfonamides: pharmacology,Transcription Factors,Transcription Factors: antagonists & inhibitors,X-Ray},
 pages = {9831-9837},
 volume = {55},
 websites = {http://dx.doi.org/10.1021/jm3010515,http://pubs.acs.org/doi/pdfplus/10.1021/jm3010515},
 publisher = {American Chemical Society},
 id = {58d737ec-f012-3915-8255-17a2a94caeb8},
 created = {2015-10-07T14:20:50.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:46.191Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Fish2012},
 source_type = {Journal Article},
 private_publication = {false},
 abstract = {The posttranslational modification of chromatin through acetylation at selected histone lysine residues is governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The significance of this subset of the epigenetic code is interrogated and interpreted by an acetyllysine-specific protein–protein interaction with bromodomain reader modules. Selective inhibition of the bromo and extra C-terminal domain (BET) family of bromodomains with a small molecule is feasible, and this may represent an opportunity for disease intervention through the recently disclosed antiproliferative and anti-inflammatory properties of such inhibitors. Herein, we describe the discovery and structure–activity relationship (SAR) of a novel, small-molecule chemical probe for BET family inhibition that was identified through the application of structure-based fragment assessment and optimization techniques. This has yielded a potent, selective compound with cell-based activity (PFI-1) that may further add to the und...},
 bibtype = {article},
 author = {Fish, Paul V. and Filippakopoulos, Panagis and Bish, Gerwyn and Brennan, Paul E. and Bunnage, Mark E. and Cook, Andrew S. and Federov, Oleg and Gerstenberger, Brian S. and Jones, Hannah and Knapp, Stefan and Marsden, Brian and Nocka, Karl and Owen, Dafydd R. and Philpott, Martin and Picaud, Sarah and Primiano, Michael J. and Ralph, Michael J. and Sciammetta, Nunzio and Trzupek, John D.},
 doi = {10.1021/jm3010515},
 journal = {Journal of Medicinal Chemistry},
 number = {22}
}

The posttranslational modification of chromatin through acetylation at selected histone lysine residues is governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The significance of this subset of the epigenetic code is interrogated and interpreted by an acetyllysine-specific protein–protein interaction with bromodomain reader modules. Selective inhibition of the bromo and extra C-terminal domain (BET) family of bromodomains with a small molecule is feasible, and this may represent an opportunity for disease intervention through the recently disclosed antiproliferative and anti-inflammatory properties of such inhibitors. Herein, we describe the discovery and structure–activity relationship (SAR) of a novel, small-molecule chemical probe for BET family inhibition that was identified through the application of structure-based fragment assessment and optimization techniques. This has yielded a potent, selective compound with cell-based activity (PFI-1) that may further add to the und...

@inbook{
 type = {inbook},
 year = {2012},
 keywords = {Chemistry and Materials Science,Drug Discovery,High-Throughput Nucleotide Sequencing,High-Throughput Nucleotide Sequencing: methods,Humans,Protein Conformation,Protein Folding,Proteins,Proteins: chemistry},
 pages = {1-32},
 volume = {336},
 websites = {http://dx.doi.org/10.1007/128_2012_326%5Cnhttp://www.ncbi.nlm.nih.gov/pubmed/22610134},
 publisher = {Springer Berlin / Heidelberg},
 id = {fb8180ee-b4e7-383e-ac17-92f8fcd24b26},
 created = {2015-10-07T14:20:51.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:45.829Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Yue2012},
 source_type = {Book Section},
 private_publication = {false},
 abstract = {Proteins are macromolecules that serve a cell's myriad processes and functions in all living organisms via dynamic interactions with other proteins, small molecules and cellular components. Genetic variations in the protein-encoding regions of the human genome account for >85% of all known Mendelian diseases, and play an influential role in shaping complex polygenic diseases. Proteins also serve as the predominant target class for the design of small molecule drugs to modulate their activity. Knowledge of the shape and form of proteins, by means of their three-dimensional structures, is therefore instrumental to understanding their roles in disease and their potentials for drug development. In this chapter we outline, with the wide readership of non-structural biologists in mind, the various experimental and computational methods available for protein structure determination. We summarize how the wealth of structure information, contributed to a large extent by the technological advances in structure determination to date, serves as a useful tool to decipher the molecular basis of genetic variations for disease characterization and diagnosis, particularly in the emerging era of genomic medicine, and becomes an integral component in the modern day approach towards rational drug development.},
 bibtype = {inbook},
 author = {Yue, Wyatt W and Froese, D Sean and Brennan, Paul E},
 doi = {10.1007/128_2012_326},
 chapter = {The Role of Protein Structural Analysis in the Next Generation Sequencing Era},
 title = {Topics in current chemistry}
}

Proteins are macromolecules that serve a cell's myriad processes and functions in all living organisms via dynamic interactions with other proteins, small molecules and cellular components. Genetic variations in the protein-encoding regions of the human genome account for >85% of all known Mendelian diseases, and play an influential role in shaping complex polygenic diseases. Proteins also serve as the predominant target class for the design of small molecule drugs to modulate their activity. Knowledge of the shape and form of proteins, by means of their three-dimensional structures, is therefore instrumental to understanding their roles in disease and their potentials for drug development. In this chapter we outline, with the wide readership of non-structural biologists in mind, the various experimental and computational methods available for protein structure determination. We summarize how the wealth of structure information, contributed to a large extent by the technological advances in structure determination to date, serves as a useful tool to decipher the molecular basis of genetic variations for disease characterization and diagnosis, particularly in the emerging era of genomic medicine, and becomes an integral component in the modern day approach towards rational drug development.

@inproceedings{
 title = {Developing chemical probes for the BET bromodomains},
 type = {inproceedings},
 year = {2012},
 volume = {243},
 websites = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000324503201772&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=4fd6f7d59a501f9b8bac2be37914c43e},
 month = {3},
 day = {25},
 id = {0c53398f-f7f2-3915-b6b1-69cd9199ec5b},
 created = {2016-12-01T10:12:01.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:46.078Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Hewings2012a},
 source_type = {CONF},
 private_publication = {false},
 bibtype = {inproceedings},
 author = {Hewings, D S and Wang, M and Philpott, M and Fedorov, O and Uttarkar, S and Filippakopoulos, P and Picaud, S and Vuppusetty, C and Marsden, B and Heightman, T D and Knapp, S and Brennan, P and Conway, S J},
 booktitle = {Abstracts of Papers of the American Chemical Society}
}

@inproceedings{
 title = {3,5-Dimethylisoxazoles inhibit the bromodomain-histone protein-protein interaction},
 type = {inproceedings},
 year = {2012},
 volume = {243},
 websites = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000324503201975&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=4fd6f7d59a501f9b8bac2be37914c43e},
 month = {3},
 day = {25},
 id = {c48e6f01-5981-3edd-8fd5-35a7e54490b3},
 created = {2016-12-01T10:12:01.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:46.075Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Hewings2012},
 source_type = {CONF},
 private_publication = {false},
 bibtype = {inproceedings},
 author = {Hewings, D S and Wang, M and Philpott, M and Fedorov, O and Uttarkar, S and Filippakopoulos, P and Picaud, S and Vuppusetty, C and Marsden, B and Heightman, T D and Knapp, S and Brennan, P and Conway, S J},
 booktitle = {ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY}
}

@inproceedings{
 title = {Developing small molecule inhibitors of the CREBBP bromodomain-histone interaction},
 type = {inproceedings},
 year = {2012},
 volume = {244},
 websites = {http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000324621806042&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=4fd6f7d59a501f9b8bac2be37914c43e},
 month = {8},
 day = {19},
 id = {12874882-dad7-373b-a3d9-52e063d67341},
 created = {2016-12-01T10:12:02.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:46.032Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Rooney2012},
 source_type = {CONF},
 private_publication = {false},
 bibtype = {inproceedings},
 author = {Rooney, T P C and Fedorov, O and Filippakopoulos, P and Wang, M and Philpott, M and Cook, A and Heightman, T D and Knapp, S and Pryde, D and Brennan, P E and Conway, S J},
 booktitle = {Abstracts of Papers of the American Chemical Society}
}

@article{
 title = {The therapeutic potential of acetyl-lysine and methyl-lysine effector domains},
 type = {article},
 year = {2012},
 volume = {9},
 month = {9},
 day = {1},
 id = {4d480fad-a7d1-394b-8895-2c997539f77e},
 created = {2016-12-01T10:12:02.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:46.396Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Brennan2012},
 source_type = {JOUR},
 private_publication = {false},
 abstract = {Epigenetic reader domains are protein interaction modules that selectively recognize common post-translational modification on histones and other nuclear proteins such as ε-N-acetylated lysine or methyllysine/arginine residues. Interactions mediated by these effector domains result in the recruitment of gene specific transcriptional regulators. This review focusses on reader domains that recognize acetylated and methylated lysine and arginine residues. Bromodomains selectively recognize acetylated lysines residues and inhibitors have recently emerged as promising lead compounds for the treatment of cancer and inflammatory diseases, acting by specifically repressing expression of oncogenes and pro-inflammatory cytokines. Initial inhibitors have also been reported for methyllysine binding domains. Here we review recent development of this emerging target area. © 2012 Elsevier Ltd. All rights reserved.},
 bibtype = {article},
 author = {Brennan, Paul and Filippakopoulos, Panagis and Knapp, Stefan},
 doi = {10.1016/j.ddstr.2012.04.001},
 journal = {Drug Discovery Today: Therapeutic Strategies},
 number = {2-3}
}

Epigenetic reader domains are protein interaction modules that selectively recognize common post-translational modification on histones and other nuclear proteins such as ε-N-acetylated lysine or methyllysine/arginine residues. Interactions mediated by these effector domains result in the recruitment of gene specific transcriptional regulators. This review focusses on reader domains that recognize acetylated and methylated lysine and arginine residues. Bromodomains selectively recognize acetylated lysines residues and inhibitors have recently emerged as promising lead compounds for the treatment of cancer and inflammatory diseases, acting by specifically repressing expression of oncogenes and pro-inflammatory cytokines. Initial inhibitors have also been reported for methyllysine binding domains. Here we review recent development of this emerging target area. © 2012 Elsevier Ltd. All rights reserved.

@article{
 title = {A tandem asymmetric synthesis approach for the efficient preparation of enantiomerically pure 9-(hydroxyethyl) anthracene},
 type = {article},
 year = {2011},
 keywords = {enantioselective hydroxyethyl anthracene prepn asy},
 pages = {253-255},
 volume = {22},
 websites = {http://ac.els-cdn.com/S0957416611000413/1-s2.0-S0957416611000413-main.pdf?_tid=26f44d872c9c311d023093bcf0156314&acdnat=1345640538_6e05dace38a9a29a846fea78cdae6cb2},
 publisher = {Elsevier Ltd.},
 id = {5e0ad96a-8246-3800-a9ce-50ce0503fe6f},
 created = {2015-10-01T17:18:19.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:45.928Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Ball2011},
 source_type = {Journal Article},
 notes = {CAPLUS AN 2011:425454(Journal)},
 private_publication = {false},
 abstract = {A tandem approach for the preparation of gram quantities of enantiomerically pure 9-(hydroxyethyl)-anthracene is presented using an asymmetric reduction followed by kinetic resolution that has potential applicability to other chiral alcohols. © 2011 Elsevier Ltd. All rights reserved.},
 bibtype = {article},
 author = {Ball, Jennifer C. and Brennan, Paul and Elsunaki, Tareg M. and Jaunet, Alexis and Jones, Simon},
 doi = {10.1016/j.tetasy.2011.01.019},
 journal = {Tetrahedron Asymmetry},
 number = {3}
}

A tandem approach for the preparation of gram quantities of enantiomerically pure 9-(hydroxyethyl)-anthracene is presented using an asymmetric reduction followed by kinetic resolution that has potential applicability to other chiral alcohols. © 2011 Elsevier Ltd. All rights reserved.

@article{
 title = {A general and mild two-step procedure for the synthesis of aryl and heteroaryl sulfonamides from the corresponding iodides},
 type = {article},
 year = {2011},
 keywords = {Acid labile groups,Oxidative chlorination,Sulfonamides,Thiobenzoates},
 pages = {820-823},
 volume = {52},
 websites = {http://ac.els-cdn.com/S0040403910022689/1-s2.0-S0040403910022689-main.pdf?_tid=dd0998fc68dba4b6635d7c6b3fdf92c8&acdnat=1345640971_bf1588dea35480baf642226e58142b2e,http://dx.doi.org/10.1016/j.tetlet.2010.12.050},
 publisher = {Elsevier Ltd.},
 id = {2cb6351a-7c24-3618-ba97-a03bc6e941cb},
 created = {2015-10-07T14:20:51.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:45.907Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Ho2011},
 source_type = {Journal Article},
 notes = {<b>From Duplicate 1 (<i>A general and mild two-step procedure for the synthesis of aryl and heteroaryl sulfonamides from the corresponding iodides</i> - Ho, Danny K H; Chan, Lily; Hooper, Alice; Brennan, Paul E)<br/></b><br/>CAPLUS AN 2011:82248(Journal)},
 private_publication = {false},
 abstract = {A mild two-step preparation of aryl and heteroaryl sulfonyl chlorides and sulfonamides from their corresponding iodides is developed. Acid labile functionalities are shown to be stable under both the copper-catalysed coupling and the subsequent oxidative chlorination. © 2010 American Chemical Society.},
 bibtype = {article},
 author = {Ho, Danny K H and Chan, Lily and Hooper, Alice and Brennan, Paul E.},
 doi = {10.1016/j.tetlet.2010.12.050},
 journal = {Tetrahedron Letters},
 number = {7}
}

A mild two-step preparation of aryl and heteroaryl sulfonyl chlorides and sulfonamides from their corresponding iodides is developed. Acid labile functionalities are shown to be stable under both the copper-catalysed coupling and the subsequent oxidative chlorination. © 2010 American Chemical Society.

@article{
 title = {Pyrimido[4,5-d]azepines as potent and selective 5-HT2Creceptor agonists: Design, synthesis, and evaluation of PF-3246799 as a treatment for urinary incontinence},
 type = {article},
 year = {2011},
 keywords = {5-HT2Creceptor agonists,5-d]azepines,PF-3246799,Pyrimido[4,Urinary incontinence},
 pages = {2715-2720},
 volume = {21},
 id = {6bf5ac91-0542-3ebb-91e9-afe2978e70fe},
 created = {2017-11-28T02:10:05.400Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2023-08-25T17:51:16.457Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Andrews2011},
 private_publication = {false},
 abstract = {New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT2Creceptor agonists. A preferred example, 7b had minimal activation at either the 5-HT2Aor 5-HT2Breceptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection. © 2010 Elsevier Ltd. All rights reserved.},
 bibtype = {article},
 author = {Andrews, Mark D. and Fish, Paul V. and Blagg, Julian and Brabham, Tiffini K. and Brennan, Paul E. and Bridgeland, Alison and Brown, Alan D. and Bungay, Peter J. and Conlon, Kelly M. and Edmunds, Nicholas J. and Af Forselles, Kerry and Gibbons, Colleen P. and Green, Martin P. and Hanton, Giles and Holbrook, Mark and Jessiman, Alan S. and McIntosh, Karin and McMurray, Gordon and Nichols, Carly L. and Root, James A. and Storer, R. Ian and Sutton, Michael R. and Ward, Robin V. and Westbrook, Dominique and Whitlock, Gavin A.},
 doi = {10.1016/j.bmcl.2010.11.120},
 journal = {Bioorganic and Medicinal Chemistry Letters},
 number = {9}
}

New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT2Creceptor agonists. A preferred example, 7b had minimal activation at either the 5-HT2Aor 5-HT2Breceptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection. © 2010 Elsevier Ltd. All rights reserved.

@article{
 title = {Catalytic and chaperone-like functions in an intrinsically disordered protein associated with desiccation tolerance},
 type = {article},
 year = {2010},
 pages = {16084-16089},
 volume = {107},
 websites = {http://www.pnas.org/cgi/doi/10.1073/pnas.1006276107},
 id = {ca78c36d-3ea3-341e-a78d-a8c227024ca9},
 created = {2015-10-01T17:18:18.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:46.118Z},
 read = {true},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Chakrabortee2010},
 source_type = {Journal Article},
 folder_uuids = {6d2d2272-3b96-49f0-8a26-aab1ab12537b},
 private_publication = {false},
 abstract = {Intrinsically disordered proteins (IDPs) lack well-defined structure but are widely represented in eukaryotic proteomes. Although the functions of most IDPs are not understood, some have been shown to have molecular recognition and/or regulatory roles where their disordered nature might be advantageous. Anhydrin is an uncharacterized IDP induced by dehydration in an anhydrobiotic nematode, Aphelenchus avenae. We show here that anhydrin is a moonlighting protein with two novel, independent functions relating to desiccation tolerance. First, it has a chaperone-like activity that can reduce desiccation-induced enzyme aggregation and inactivation in vitro. When expressed in a human cell line, anhydrin localizes to the nucleus and reduces the propensity of a polyalanine expansion protein associated with oculopharyngeal muscular dystrophy to form aggregates. This in vivo activity is distinguished by a loose association of anhydrin with its client protein, consistent with a role as a molecular shield. In addition, anhydrin exhibits a second function as an endonuclease whose substrates include supercoiled, linear, and chromatin linker DNA. This nuclease activity could be involved in either repair of desiccation-induced DNA damage incurred during anhydrobiosis or in apoptotic or necrotic processes, for example, but it is particularly unexpected for anhydrin because IDP functions defined to date anticorrelate with enzyme activity. Enzymes usually require precise three-dimensional positioning of residues at the active site, but our results suggest this need not be the case. Anhydrin therefore extends the range of IDP functional categories to include catalysis and highlights the potential for the discovery of new functions in disordered proteomes.},
 bibtype = {article},
 author = {Chakrabortee, S. and Meersman, F. and Kaminski Schierle, G. S. and Bertoncini, C. W. and McGee, B. and Kaminski, C. F. and Tunnacliffe, A.},
 doi = {10.1073/pnas.1006276107},
 journal = {Proceedings of the National Academy of Sciences},
 number = {37}
}

Intrinsically disordered proteins (IDPs) lack well-defined structure but are widely represented in eukaryotic proteomes. Although the functions of most IDPs are not understood, some have been shown to have molecular recognition and/or regulatory roles where their disordered nature might be advantageous. Anhydrin is an uncharacterized IDP induced by dehydration in an anhydrobiotic nematode, Aphelenchus avenae. We show here that anhydrin is a moonlighting protein with two novel, independent functions relating to desiccation tolerance. First, it has a chaperone-like activity that can reduce desiccation-induced enzyme aggregation and inactivation in vitro. When expressed in a human cell line, anhydrin localizes to the nucleus and reduces the propensity of a polyalanine expansion protein associated with oculopharyngeal muscular dystrophy to form aggregates. This in vivo activity is distinguished by a loose association of anhydrin with its client protein, consistent with a role as a molecular shield. In addition, anhydrin exhibits a second function as an endonuclease whose substrates include supercoiled, linear, and chromatin linker DNA. This nuclease activity could be involved in either repair of desiccation-induced DNA damage incurred during anhydrobiosis or in apoptotic or necrotic processes, for example, but it is particularly unexpected for anhydrin because IDP functions defined to date anticorrelate with enzyme activity. Enzymes usually require precise three-dimensional positioning of residues at the active site, but our results suggest this need not be the case. Anhydrin therefore extends the range of IDP functional categories to include catalysis and highlights the potential for the discovery of new functions in disordered proteomes.

@article{
 title = {Potent and selective α1Aadrenoceptor partial agonists-Novel imidazole frameworks},
 type = {article},
 year = {2009},
 keywords = {Partial agonist,α1AAdrenergic receptor},
 pages = {3118-3121},
 volume = {19},
 websites = {http://ac.els-cdn.com/S0960894X09004867/1-s2.0-S0960894X09004867-main.pdf?_tid=7573847fd1f20ad30107dbf97af3b63d&acdnat=1345645678_e85a25ffff5518bbf16209a42114f2ac},
 publisher = {Elsevier B.V.},
 id = {c1632b4e-b510-3e68-adce-aa840632cf00},
 created = {2015-10-01T17:18:09.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:46.233Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Whitlock2009},
 source_type = {Journal Article},
 notes = {CAPLUS AN 2009:603827(Journal)},
 private_publication = {false},
 abstract = {Novel imidazole frameworks have been identified as potent partial agonists of the α1Aadrenergic receptor, with good selectivity over the α1B, α1Dand α2Areceptor sub-types. Nitrile 28 possessed attractive CNS drug-like properties with good membrane permeability and no P-pg mediated efflux. 28 also possessed excellent solubility, metabolic stability and wide ligand selectivity. © 2009 Elsevier Ltd. All rights reserved.},
 bibtype = {article},
 author = {Whitlock, Gavin A. and Brennan, Paul E. and Roberts, Lee R. and Stobie, Alan},
 doi = {10.1016/j.bmcl.2009.03.162},
 journal = {Bioorganic and Medicinal Chemistry Letters},
 number = {11}
}

Novel imidazole frameworks have been identified as potent partial agonists of the α1Aadrenergic receptor, with good selectivity over the α1B, α1Dand α2Areceptor sub-types. Nitrile 28 possessed attractive CNS drug-like properties with good membrane permeability and no P-pg mediated efflux. 28 also possessed excellent solubility, metabolic stability and wide ligand selectivity. © 2009 Elsevier Ltd. All rights reserved.

@article{
 title = {Discovery of a novel azepine series of potent and selective 5-HT2Cagonists as potential treatments for urinary incontinence},
 type = {article},
 year = {2009},
 keywords = {5-HT2C agonist,Azepine,Serotonin receptor agonist,Stress urinary incontinence},
 pages = {4999-5003},
 volume = {19},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/19646865,http://www.sciencedirect.com/science/article/pii/S0960894X0901021X,http://ac.els-cdn.com/S0960894X0901021X/1-s2.0-S0960894X0901021X-main.pdf?_tid=3395dbd8-d29e-11e2-9507-00000aacb35e&acdnat=1370958948_cd21fa819e},
 publisher = {Elsevier Ltd},
 id = {9e73d9b4-77ee-38df-bf32-d20f753ae8fb},
 created = {2015-10-07T14:20:51.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:45.735Z},
 read = {false},
 starred = {true},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Brennan2009},
 source_type = {Journal Article},
 private_publication = {false},
 abstract = {A range of heterocycle fused azepines were synthesized in order to find a CNS penetrant, selective 5-HT2Cagonist for the treatment of incontinence. The pyridazo-azepines such as compound 11 were shown to be potent 5-HT2Cagonists and have potential for CNS penetration and good in vitro ADME properties but lacked selectivity against 5-HT2B. Fusing a further heterocycle gave the selective triazolopyrimido-azepines. An example of this series, compound 36, was shown to be potent, selective, metabolically stable in vitro and efficacious in an in vivo model of stress urinary incontinence. © 2009.},
 bibtype = {article},
 author = {Brennan, Paul E. and Whitlock, Gavin A. and Ho, Danny K H and Conlon, Kelly and McMurray, Gordon},
 doi = {10.1016/j.bmcl.2009.07.063},
 journal = {Bioorganic and Medicinal Chemistry Letters},
 number = {17}
}

A range of heterocycle fused azepines were synthesized in order to find a CNS penetrant, selective 5-HT2Cagonist for the treatment of incontinence. The pyridazo-azepines such as compound 11 were shown to be potent 5-HT2Cagonists and have potential for CNS penetration and good in vitro ADME properties but lacked selectivity against 5-HT2B. Fusing a further heterocycle gave the selective triazolopyrimido-azepines. An example of this series, compound 36, was shown to be potent, selective, metabolically stable in vitro and efficacious in an in vivo model of stress urinary incontinence. © 2009.

@article{
 title = {Total Synthesis of rapamycin},
 type = {article},
 year = {2009},
 keywords = {Anticancer agents,Immunosuppressive agents,Macrocyclization,Natural products,Total synthesis},
 pages = {2874-2914},
 volume = {15},
 websites = {http://onlinelibrary.wiley.com/store/10.1002/chem.200801656/asset/2874_ftp.pdf?v=1&t=h66fxp71&s=17e1224c9c77aef48361320c71c9603a00466463},
 publisher = {Wiley-VCH Verlag GmbH & Co. KGaA},
 id = {6c91e401-ccbd-30a0-b766-9dfcadc8a194},
 created = {2015-10-07T14:20:51.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:45.826Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Ley2009},
 source_type = {Journal Article},
 notes = {<b>From Duplicate 2 (<i>Total synthesis of rapamycin</i> - Ley, Steven V; Tackett, Miles N; Maddess, Matthew L; Anderson, James C; Brennan, Paul E; Cappi, Michael W; Heer, Jag P; Helgen, Celine; Kori, Masakuni; Kouklovsky, Cyrille; Marsden, Stephen P; Norman, Joanne; Osborn, David P; Palomero, Maria A; Pavey, John B J; Pinel, Catherine; Robinson, Lesley A; Schnaubelt, Jurgen; Scott, James S; Spilling, Christopher D; Watanabe, Hidenori; Wesson, Kieron E; Willis, Michael C)<br/></b><br/>CAPLUS AN 2009:365301(Journal)},
 private_publication = {false},
 abstract = {For over 30 years, rapamycin has generated a sustained and intense interest from the scientific community as a result of its exceptional pharmacological properties and challenging structural features. In addition to its well known therapeutic value as a potent immunosuppressive agent, rapamycin and its derivatives have recently gained prominence for the treatment of a wide variety of other human malignancies. Herein we disclose full details of our extensive investigation into the synthesis of rapamycin that culminated in a new and convergent preparation featuring a macro-etherification/catechol-templating strategy for construction of the macrocyclic core of this natural product.},
 bibtype = {article},
 author = {Ley, Steven V. and Tackett, Miles N. and Maddess, Matthew L. and Anderson, James C. and Brennan, Paul E. and Cappi, Michael W. and Heer, Jag P. and Helgen, Céline and Kori, Masakuni and Kouklovsky, Cyrille and Marsden, Stephen P. and Norman, Joanne and Osborn, David P. and Palomero, María Á and Pavey, John B.J. and Pinel, Catherine and Robinson, Lesley A. and Schnaubelt, Jürgen and Scott, James S. and Spilling, Christopher D. and Watanabe, Hidenori and Wesson, Kieron E. and Willis, Michael C.},
 doi = {10.1002/chem.200801656},
 journal = {Chemistry - A European Journal},
 number = {12}
}

For over 30 years, rapamycin has generated a sustained and intense interest from the scientific community as a result of its exceptional pharmacological properties and challenging structural features. In addition to its well known therapeutic value as a potent immunosuppressive agent, rapamycin and its derivatives have recently gained prominence for the treatment of a wide variety of other human malignancies. Herein we disclose full details of our extensive investigation into the synthesis of rapamycin that culminated in a new and convergent preparation featuring a macro-etherification/catechol-templating strategy for construction of the macrocyclic core of this natural product.

@misc{
 title = {Preparation of pyrimido[4,5-d]azepine derivatives as 5-HT2C agonists},
 type = {misc},
 year = {2008},
 keywords = {pyrimidoazepine prepn serotonin 5HT2C receptor ago},
 pages = {180pp.},
 issue = {Copyright (C) 2012 American Chemical Society (ACS). All Rights Reserved.},
 publisher = {Pfizer Limited, UK .},
 revision = {WO 2008117169 A1},
 id = {88574e90-5df6-3709-ba49-990536f85b45},
 created = {2015-10-01T17:18:19.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:45.913Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Andrews2008},
 source_type = {Patent},
 notes = {CAPLUS AN 2008:1185770(Patent)},
 private_publication = {false},
 abstract = {The title compds. I [R1 = H, alkyl, fluoroalkyl, cycloalkyl, etc.; R2 = (CH2)pPh, CHR6Ph, NR7R8, etc.; R31, R32, R33, R34 = H, alkyl, fluoroalkyl; R6 = alkyl, fluoroalkyl, OH or F; R7 = alkyl, fluoroalkyl, cycloalkyl or fluorocycloalkyl; R8 = alkyl, fluoroalkyl, cycloalkyl, cycloalkylmethyl or fluorocycloalkyl; or NR7R8 = 4-6 membered heterocyclyl optionally comprising 1 further heteroatom selected from O and S (said ring being optionally fused to a Ph ring); p = 1-2; R100 = H or NH prodrug moiety] which act as 5-HT2C agonists, were prepd. E.g., a multi-step synthesis of II, starting from 1-tert-Bu 4-Et 5-oxoazepane-1,4-dicarboxylate and 2-phenylacetamidine, was given. II showed Ki of 72.0 nM when tested for 5-HT2C agonistic activity. Pharmaceutical compn. comprising the compd. I is disclosed. [on SciFinder(R)]},
 bibtype = {misc},
 author = {Andrews, Mark David and Blagg, Julian and Brennan, Paul Edward and Fish, Paul Vincent and Roberts, Lee Richard and Storer, Robert Ian and Whitlock, Gavin Alistair}
}

The title compds. I [R1 = H, alkyl, fluoroalkyl, cycloalkyl, etc.; R2 = (CH2)pPh, CHR6Ph, NR7R8, etc.; R31, R32, R33, R34 = H, alkyl, fluoroalkyl; R6 = alkyl, fluoroalkyl, OH or F; R7 = alkyl, fluoroalkyl, cycloalkyl or fluorocycloalkyl; R8 = alkyl, fluoroalkyl, cycloalkyl, cycloalkylmethyl or fluorocycloalkyl; or NR7R8 = 4-6 membered heterocyclyl optionally comprising 1 further heteroatom selected from O and S (said ring being optionally fused to a Ph ring); p = 1-2; R100 = H or NH prodrug moiety] which act as 5-HT2C agonists, were prepd. E.g., a multi-step synthesis of II, starting from 1-tert-Bu 4-Et 5-oxoazepane-1,4-dicarboxylate and 2-phenylacetamidine, was given. II showed Ki of 72.0 nM when tested for 5-HT2C agonistic activity. Pharmaceutical compn. comprising the compd. I is disclosed. [on SciFinder(R)]

@article{
 title = {Total synthesis of rapamycin},
 type = {article},
 year = {2007},
 keywords = {Antitumor agents,Immunosuppressants,Macrocyclization,Natural products,Total synthesis},
 pages = {591-597},
 volume = {46},
 websites = {http://onlinelibrary.wiley.com/store/10.1002/anie.200604053/asset/591_ftp.pdf?v=1&t=h66fyv71&s=5d3b06cd57d32b388476999713af947cac841de8},
 publisher = {Wiley-VCH Verlag GmbH & Co. KGaA},
 id = {4a37ee91-9505-3c0e-af07-402761fdbda4},
 created = {2015-10-07T14:20:51.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:45.843Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Maddess2007},
 source_type = {Journal Article},
 notes = {<b>From Duplicate 2 (<i>Total synthesis of rapamycin</i> - Maddess, Matthew L; Tackett, Miles N; Watanabe, Hidenori; Brennan, Paul E; Spilling, Christopher D; Scott, James S; Osborn, David P; Ley, Steven V)<br/></b><br/>CAPLUS AN 2007:103751(Journal)},
 private_publication = {false},
 abstract = {For over 30 years, rapamycin has generated a sustained and intense interest from the scientific community as a result of its exceptional pharmacological properties and challenging structural features. In addition to its well known therapeutic value as a potent immunosuppressive agent, rapamycin and its derivatives have recently gained prominence for the treatment of a wide variety of other human malignancies. Herein we disclose full details of our extensive investigation into the synthesis of rapamycin that culminated in a new and convergent preparation featuring a macro-etherification/catechol-templating strategy for construction of the macrocyclic core of this natural product.},
 bibtype = {article},
 author = {Maddess, Matthew L. and Tackett, Miles N. and Watanabe, Hidenori and Brennan, Paul E. and Spilling, Christopher D. and Scott, James S. and Osborn, David P. and Ley, Steven V.},
 doi = {10.1002/anie.200604053},
 journal = {Angewandte Chemie - International Edition},
 number = {4}
}

For over 30 years, rapamycin has generated a sustained and intense interest from the scientific community as a result of its exceptional pharmacological properties and challenging structural features. In addition to its well known therapeutic value as a potent immunosuppressive agent, rapamycin and its derivatives have recently gained prominence for the treatment of a wide variety of other human malignancies. Herein we disclose full details of our extensive investigation into the synthesis of rapamycin that culminated in a new and convergent preparation featuring a macro-etherification/catechol-templating strategy for construction of the macrocyclic core of this natural product.

@misc{
 title = {Aminopyrimidine compounds as polo-like kinase 1 inhibitors and their preparation, pharmaceutical compositions and use for treatment of cancer},
 type = {misc},
 year = {2006},
 keywords = {aminopyrimidine prepn polo like kinase inhibitor p,treatment cancer plk1 inhibitor aminopyridine prep},
 pages = {151 pp.},
 publisher = {Amgen, Inc., USA .},
 revision = {WO 2006066172 A1},
 id = {c957bb4a-492a-3105-8a85-e73a6629e21e},
 created = {2015-10-01T17:18:19.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2023-08-25T17:51:16.417Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Smith2006},
 source_type = {Patent},
 notes = {CAPLUS AN 2006:605439(Patent)},
 private_publication = {false},
 abstract = {The invention relates to aminopyrimidine compds. of formula I, which are useful for treating diseases mediated by polo-like kinase 1 (Plk1). The invention also relates to the therapeutic use of such aminopyrimidine compds. and compns. thereof in treating disease states assocd. with abnormal cell growth and unwanted cell proliferation. Compds. of formula I wherein X1 is CR1 or N; X2 is CH or N; Y is O, S, CHR7 or NR7; W is CN, (un)substituted imidazolidine, (un)substituted imidazoline, or (un)substituted tetrahydropyrimidine; R1 and R2 are independently H, halo, CN, (un)substituted C1-6 alkyl, (un)substituted alkyl(hetero)aryl, etc.; R3 is H, OH, halo, NO2, NH2, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, or (hetero)aryl; R4 and R7 are independently H or C1-6 alkyl; n is an integer from 1 to 6; and their pharmaceutically acceptable salts, hydrates and stereoisomers are claimed. Example compd. II was prepd. by substitution of 4-(5-bromothien-2-yl)-2-chloropyrimidine with 1-(2-aminoethyl)imidazolidin-2-one. Addnl. 464 example compds. were prepd. in this invention. All the invention compds. were evaluated for their human polo-like kinase 1 inhibitory activity. From the assay, it was detd. that all the example compds. exhibited plk1 activity with IC50 values less than 1 μM. [on SciFinder(R)]},
 bibtype = {misc},
 author = {Smith, Adrian Leonard and Brennan, Paul Edward and Demorin, Frenel Fils and Liu, Gang and Paras, Nick A and Retz, Daniel Martin}
}

The invention relates to aminopyrimidine compds. of formula I, which are useful for treating diseases mediated by polo-like kinase 1 (Plk1). The invention also relates to the therapeutic use of such aminopyrimidine compds. and compns. thereof in treating disease states assocd. with abnormal cell growth and unwanted cell proliferation. Compds. of formula I wherein X1 is CR1 or N; X2 is CH or N; Y is O, S, CHR7 or NR7; W is CN, (un)substituted imidazolidine, (un)substituted imidazoline, or (un)substituted tetrahydropyrimidine; R1 and R2 are independently H, halo, CN, (un)substituted C1-6 alkyl, (un)substituted alkyl(hetero)aryl, etc.; R3 is H, OH, halo, NO2, NH2, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, or (hetero)aryl; R4 and R7 are independently H or C1-6 alkyl; n is an integer from 1 to 6; and their pharmaceutically acceptable salts, hydrates and stereoisomers are claimed. Example compd. II was prepd. by substitution of 4-(5-bromothien-2-yl)-2-chloropyrimidine with 1-(2-aminoethyl)imidazolidin-2-one. Addnl. 464 example compds. were prepd. in this invention. All the invention compds. were evaluated for their human polo-like kinase 1 inhibitory activity. From the assay, it was detd. that all the example compds. exhibited plk1 activity with IC50 values less than 1 μM. [on SciFinder(R)]

@inproceedings{
 title = {Studies toward a total synthesis of bengazole A utilizing BDA-protected building blocks.},
 type = {inproceedings},
 year = {2003},
 pages = {ORGN-418},
 id = {bb64938e-f421-3558-9358-49d964b25ec3},
 created = {2015-10-01T17:16:54.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:46.432Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Balskus2003},
 private_publication = {false},
 abstract = {The members of the bengazole family of marine metabolites are noteworthy among oxazole-contg. natural products, not only for their diverse biol. activities, but also due to their unusual structural features. Bengazole A is a particularly interesting synthetic target due to its potent anti-fungal and anthelmentic activity. Our retrosynthesis of bengazole A disconnects the target back to three key intermediates (1-3). We plan to couple BDA-protected allylic diol 3 and the nitrile oxide derived from known oxime 2 via a diastereoselective 1,3-dipolar cycloaddn. After deprotection of the cycloadduct, amide formation with acid 1, followed by cyclization/dehydration, will form the 2,4-substituted oxazole and complete the construction of the carbon skeleton of the natural product. We have synthesized all key intermediates; our routes employ convenient, BDA-protected building blocks. These BDA-protected intermediates offer many advantages over traditional acetonides, including increased stability and ease of handling. [on SciFinder(R)]},
 bibtype = {inproceedings},
 author = {Balskus, Emily P and Brennan, Paul E and Ley, Steven V},
 booktitle = {Abstracts of Papers, 225th ACS National Meeting, New Orleans, LA, United States, March 23-27, 2003}
}

The members of the bengazole family of marine metabolites are noteworthy among oxazole-contg. natural products, not only for their diverse biol. activities, but also due to their unusual structural features. Bengazole A is a particularly interesting synthetic target due to its potent anti-fungal and anthelmentic activity. Our retrosynthesis of bengazole A disconnects the target back to three key intermediates (1-3). We plan to couple BDA-protected allylic diol 3 and the nitrile oxide derived from known oxime 2 via a diastereoselective 1,3-dipolar cycloaddn. After deprotection of the cycloadduct, amide formation with acid 1, followed by cyclization/dehydration, will form the 2,4-substituted oxazole and complete the construction of the carbon skeleton of the natural product. We have synthesized all key intermediates; our routes employ convenient, BDA-protected building blocks. These BDA-protected intermediates offer many advantages over traditional acetonides, including increased stability and ease of handling. [on SciFinder(R)]

@article{
 title = {Synthesis of carbohydrate derivatives using solid-phase work-up and scavenging techniques},
 type = {article},
 year = {2003},
 keywords = {glycosylation solid phase purifn,oligosaccharide solid phase prepn purifn},
 pages = {2029-2031},
 volume = {1},
 websites = {http://pubs.rsc.org/en/content/articlepdf/2003/ob/b303951j},
 publisher = {Royal Society of Chemistry},
 id = {a10dd405-fa4a-372e-a6e0-98110a6980e6},
 created = {2015-10-01T17:17:59.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:46.210Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {MacCoss2003},
 source_type = {Journal Article},
 notes = {CAPLUS AN 2003:491901(Journal)},
 private_publication = {false},
 abstract = {Methods to allow the clean prepn. of oligosaccharides were investigated using techniques that do not require conventional column chromatog. or an aq. work-up. The route was designed to provide rapid access to oligosaccharides and is suitable for automation and parallel library formation. The research has focused on the glycosidations of a range of glycosyl acceptors with various selenophenyl glycosyl donors using iodine as an activator in the presence of DTBMP, a hindered org. base. Hydroxyl-contg. contaminants were removed by scavenging with polymer-supported tosyl chloride. [on SciFinder(R)]},
 bibtype = {article},
 author = {MacCoss, Rachel N. and Brennan, Paul E. and Ley, Steven V.},
 doi = {10.1039/b303951j},
 journal = {Organic and Biomolecular Chemistry},
 number = {12}
}

Methods to allow the clean prepn. of oligosaccharides were investigated using techniques that do not require conventional column chromatog. or an aq. work-up. The route was designed to provide rapid access to oligosaccharides and is suitable for automation and parallel library formation. The research has focused on the glycosidations of a range of glycosyl acceptors with various selenophenyl glycosyl donors using iodine as an activator in the presence of DTBMP, a hindered org. base. Hydroxyl-contg. contaminants were removed by scavenging with polymer-supported tosyl chloride. [on SciFinder(R)]

@article{
 title = {Palladium-containing perovskites: recoverable and reuseable catalysts for Suzuki couplingsElectronic supplementary information (ESI) available: experimental details. See http://www.rsc.org/suppdata/cc/b3/b308465e/},
 type = {article},
 year = {2003},
 keywords = {aryl halide arylboronic acid Suzuki cross coupling,biaryl prepn,palladium perovskite Suzuki cross coupling catalys},
 pages = {2652},
 volume = {3},
 websites = {http://xlink.rsc.org/?DOI=b308465e},
 publisher = {Royal Society of Chemistry},
 id = {9e043e8e-22a8-326b-8e43-45a41f867f6b},
 created = {2015-10-07T14:20:51.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-07-09T12:39:50.637Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Smith2003},
 source_type = {Journal Article},
 notes = {<b>From Duplicate 1 (<i>Palladium-containing perovskites: recoverable and reuseable catalysts for Suzuki couplings</i> - Smith, Martin D; Stepan, Antonia F; Ramarao, Chandrashekar; Brennan, Paul E; Ley, Steven V)<br/></b><br/>CAPLUS AN 2003:823792(Journal)},
 private_publication = {false},
 abstract = {Palladium-containing perovskites (LaFe0.57Co0.38Pd0.05O3) have been exploited as recoverable and reuseable catalysts in Suzuki coupling reactions; residual levels of Pd after removal of the catalyst by filtration are low (2 ppm) despite evidence that the reaction is occurring via a homogeneous process.},
 bibtype = {article},
 author = {Smith, Martin D. and Stepan, Antonia F. and Ramarao, Chandrashekar and Brennan, Paul E. and Ley, Steven V.},
 doi = {10.1039/b308465e},
 journal = {Chemical Communications},
 number = {21}
}

Palladium-containing perovskites (LaFe0.57Co0.38Pd0.05O3) have been exploited as recoverable and reuseable catalysts in Suzuki coupling reactions; residual levels of Pd after removal of the catalyst by filtration are low (2 ppm) despite evidence that the reaction is occurring via a homogeneous process.

@article{
 title = {Combinatorial synthetic design. Solution and polymer-supported synthesis of heterocycles via intramolecular aza Diels-Alder and imino alcohol cyclizations},
 type = {article},
 year = {2002},
 keywords = {Alcohols,Alcohols: chemistry,Combinatorial Chemistry Techniques,Heterocyclic Compounds,Heterocyclic Compounds: chemical synthesis,alkene contg aldehyde prepn condensation arom amin,arom amine aldehyde condensation stereoselective a,benzoxazepine stereoselective prepn,condensation alkene contg aldehyde arom amine ster,fused quinoline stereoselective prepn,potential combinatorial use fused quinoline benzox,soln solid phase aza Diels Alder cycloaddn amine a},
 pages = {516-522},
 volume = {4},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/12217025,http://pubs.acs.org/doi/pdfplus/10.1021/cc020027%2B},
 publisher = {American Chemical Society},
 id = {2649102e-2bc0-395f-bd5f-d32c494ce5cc},
 created = {2015-10-07T14:20:51.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:45.804Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Spaller2002},
 source_type = {Journal Article},
 notes = {<b>From Duplicate 2 (<i>Combinatorial Synthetic Design. Solution and Polymer-Supported Synthesis of Heterocycles via Intramolecular Aza Diels-Alder and Imino Alcohol Cyclizations</i> - Spaller, Mark R; Thielemann, Wolfgang T; Brennan, Paul E; Bartlett, Paul A)<br/></b><br/>CAPLUS AN 2002:608591(Journal)},
 private_publication = {false},
 abstract = {Soln.-phase and polymer-bound cyclization reactions are presented as a method for the stereoselective prepn. of tetrahydroquinolines and tetrahydrobenzoxazepines with multiple points of variation as a potential method for combinatorial synthesis. Aldehydes connected to pendant alkenes undergo condensation with arom. amines to give iminium ions which can either react intramol. by aza-Diels-Alder cycloaddn. reactions with pendant alkenes to give fused tetrahydroquinolines such as pyrroloquinoline I or intermolecularly with amino alcs. to give fused pyrrolidinones such as II. The stepwise nature of the cyclizations allows the reactivity to be varied through the presence or absence of external nucleophiles. Salicylaldehyde-derived aldehydes, amides and esters of glyoxalic acid, and aldehydes derived from L-amino acids are used as the aldehyde components; this allows potential variability at the aldehyde, linker, and alkene moieties. Aza-Diels-Alder cycloaddn. reactions give products with up to four stereocenters; the products of cycloaddn. are racemic, even when aldehydes derived from L-amino acids are used as aldehyde substrates. Addn. of amino alcs. also gives racemic product except when D- or L-alaninol is used as the amino alc. component. The aza-Diels-Alder cycloaddn. of the aminoaldehydes is adapted and optimized for solid phase synthesis. [on SciFinder(R)]},
 bibtype = {article},
 author = {Spaller, Mark R. and Thielemann, Wolfgang T. and Brennan, Paul E. and Bartlett, Paul A.},
 doi = {10.1021/cc020027+},
 journal = {Journal of Combinatorial Chemistry},
 number = {5}
}

Soln.-phase and polymer-bound cyclization reactions are presented as a method for the stereoselective prepn. of tetrahydroquinolines and tetrahydrobenzoxazepines with multiple points of variation as a potential method for combinatorial synthesis. Aldehydes connected to pendant alkenes undergo condensation with arom. amines to give iminium ions which can either react intramol. by aza-Diels-Alder cycloaddn. reactions with pendant alkenes to give fused tetrahydroquinolines such as pyrroloquinoline I or intermolecularly with amino alcs. to give fused pyrrolidinones such as II. The stepwise nature of the cyclizations allows the reactivity to be varied through the presence or absence of external nucleophiles. Salicylaldehyde-derived aldehydes, amides and esters of glyoxalic acid, and aldehydes derived from L-amino acids are used as the aldehyde components; this allows potential variability at the aldehyde, linker, and alkene moieties. Aza-Diels-Alder cycloaddn. reactions give products with up to four stereocenters; the products of cycloaddn. are racemic, even when aldehydes derived from L-amino acids are used as aldehyde substrates. Addn. of amino alcs. also gives racemic product except when D- or L-alaninol is used as the amino alc. component. The aza-Diels-Alder cycloaddn. of the aminoaldehydes is adapted and optimized for solid phase synthesis. [on SciFinder(R)]

@article{
 title = {New catalysts for olefin metathesis.},
 type = {article},
 year = {2001},
 keywords = {review olefin metathesis catalyst},
 pages = {88-93},
 volume = {14},
 publisher = {Data Trace Publishing Co.},
 id = {f4437512-8ef4-3f4d-9995-38e8a3f1789d},
 created = {2015-10-01T17:17:56.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:46.029Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Brennan2001},
 source_type = {Journal Article},
 notes = {CAPLUS AN 2001:276381(Journal; General Review)},
 private_publication = {false},
 abstract = {The title research of M. Scholl, et al. (1999), A. K. Chatterjee and R. H. Grubbs (1999), A. K. Chatterjee, et al. (2000) and C. W. Lee and R. H. Grubbs (2000) is reviewed with commentary and over 3 refs. [on SciFinder(R)]},
 bibtype = {article},
 author = {Brennan, P E and Ley, S V},
 journal = {Chemtracts: Organic Chemistry},
 number = {2}
}

The title research of M. Scholl, et al. (1999), A. K. Chatterjee and R. H. Grubbs (1999), A. K. Chatterjee, et al. (2000) and C. W. Lee and R. H. Grubbs (2000) is reviewed with commentary and over 3 refs. [on SciFinder(R)]

@book{
 title = {Phosphinate Inhibitors of Peptidoglycan Biosynthesis: Development of of a New Ring System for Combinatorial Chemistry},
 type = {book},
 year = {2000},
 websites = {http://books.google.co.uk/books?id=LuavHwAACAAJ},
 publisher = {University of California, Berkeley},
 id = {2d4cec58-b8fb-308a-b255-ec12999ad304},
 created = {2015-10-01T17:18:05.000Z},
 file_attached = {false},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:46.031Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Brennan2000},
 source_type = {Book},
 private_publication = {false},
 bibtype = {book},
 author = {Brennan, P E}
}

@article{
 title = {Application of the intramolecular azomethine imine cycloaddition to the construction of a novel, orthogonally protected spirodiamino acid scaffold},
 type = {article},
 year = {1999},
 keywords = {Azomethine imine,Combinatorial chemistry,Intramolecular dipolar cycloaddition},
 pages = {2907-2908},
 volume = {40},
 websites = {http://ac.els-cdn.com/S0040403999003913/1-s2.0-S0040403999003913-main.pdf?_tid=af2f7520379c30b77ee94519e36e3cd5&acdnat=1345640752_fee1324a179d50e72045a8799ac97ad9,http://www.sciencedirect.com/science/article/pii/S0040403999003913},
 publisher = {Elsevier Science Ltd.},
 id = {3cf7d579-0a19-3dd4-ac66-e5288cec0cd8},
 created = {2015-10-07T14:20:51.000Z},
 file_attached = {true},
 profile_id = {64f7fb50-d000-335d-a02d-06c5f340a97a},
 last_modified = {2018-09-03T10:20:45.707Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {true},
 hidden = {false},
 citation_key = {Dolle1999},
 source_type = {Journal Article},
 notes = {<b>From Duplicate 1 (<i>Application of the intramolecular azomethine imine cycloaddition to the construction of a novel, orthogonally protected spirodiamino acid scaffold</i> - Dolle, Roland E; Barden, Michael C; Brennan, Paul E; Ahmed, Gulzar; Tran, Vinh; Ho, Douglas M)<br/></b><br/>CAPLUS AN 1999:240164(Journal)},
 private_publication = {false},
 abstract = {Hydrazone 4 undergoes tandem intramolecular Michael addition - intramolecular azomethine imine cyctoaddition in ethanol at reflux to furnish the tricyclic pyrazoline methyl ester 3 in 75% yield. A five-step conversion of 3 to N1-Alloc-6-(N-Boc-aminomethyl)-1-azaspiro[4.4]nonane-2-acetic acid 1 provides access to a unique tri-functionalized scaffold for combinatorial chemistry.},
 bibtype = {article},
 author = {Dolle, Roland E. and Barden, Michael C. and Brennan, Paul E. and Ahmed, Gulzar and Tran, Vinh and Ho, Douglas M.},
 doi = {10.1016/S0040-4039(99)00391-3},
 journal = {Tetrahedron Letters},
 number = {15}
}

Hydrazone 4 undergoes tandem intramolecular Michael addition - intramolecular azomethine imine cyctoaddition in ethanol at reflux to furnish the tricyclic pyrazoline methyl ester 3 in 75% yield. A five-step conversion of 3 to N1-Alloc-6-(N-Boc-aminomethyl)-1-azaspiro[4.4]nonane-2-acetic acid 1 provides access to a unique tri-functionalized scaffold for combinatorial chemistry.