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Ming-ming Zhou - One of the best experts on this subject based on the ideXlab platform.
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The Bromodomain: A New Target in Emerging Epigenetic Medicine
ACS chemical biology, 2015Co-Authors: Steven G. Smith, Ming-ming ZhouAbstract:The Bromodomain (BrD) is a conserved protein modular domain found in many chromatin- and transcription-associated proteins that has the ability to recognize acetylated lysine residues. This activity allows Bromodomains to play a vital role in many acetylation-mediated protein–protein interactions in the cell, ranging from substrate recruitment for histone acetyltransferases (HATs) to aiding in multiple-protein complex assembly for gene transcriptional activation or suppression in chromatin. In recent years, considerable efforts have been made to develop chemical inhibitors of these Bromodomains in an effort to probe their cellular functions. Potent and selective inhibitors have been extensively developed for one group of the Bromodomain family termed BET proteins that consist of tandem Bromodomains followed by an extra terminal domain. Drug developers are actively designing inhibitors of other Bromodomains and working to move the most successful inhibitors into the clinic.
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Privileged diazepine compounds and their emergence as Bromodomain inhibitors.
Chemistry & biology, 2014Co-Authors: Steven G. Smith, Roberto Sanchez, Ming-ming ZhouAbstract:Chemical compounds built on a diazepine scaffold have recently emerged as potent inhibitors of the acetyl-lysine binding activity of Bromodomain-containing proteins, which is required for gene transcriptional activation in cancer and inflammation. Not only have these chemical compounds validated Bromodomains as attractive epigenetic drug targets, but they have also brought to the forefront another application of the diazepine, which had already been regarded as a versatile chemical scaffold in rational drug design. This article reviews the success of diazepine compounds as therapeutic agents and examines the unique chemical and geometric features of this privileged scaffold that make it an excellent template for developing potent and selective molecules that control Bromodomain-related gene expression in human diseases.
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The Bromodomain: from epigenome reader to druggable target.
Biochimica et biophysica acta, 2014Co-Authors: Roberto Sanchez, Jamel Meslamani, Ming-ming ZhouAbstract:Lysine acetylation is a fundamental post-translational modification that plays an important role in the control of gene transcription in chromatin in an ordered fashion. The Bromodomain, the conserved structural module present in transcription-associated proteins, functions exclusively to recognize acetyl-lysine on histones and non-histone proteins. The structural analyses of Bromodomains' recognition of lysine-acetylated peptides derived from histones and cellular proteins provide detailed insights into the differences and unifying features of biological ligand binding selectivity by the Bromodomains. Newly developed small-molecule inhibitors targeting Bromodomain proteins further highlight the functional importance of Bromodomain/acetyl-lysine binding as a key mechanism in orchestrating molecular interactions and regulation in chromatin biology and gene transcription. These new studies argue that modulating Bromodomain/acetyl-lysine interactions with small-molecule chemicals offer new opportunities to control gene expression in a wide array of human diseases including cancer and inflammation. This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function.
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scaling the druggability landscape of human Bromodomains a new class of drug targets
Journal of Medicinal Chemistry, 2012Co-Authors: Guangtao Zhang, Roberto Sanchez, Ming-ming ZhouAbstract:Gene transcriptional activation of the human genome in response to physiological and environmental stimuli requires chromatin structure changes defined by enzymes that modify chromatin and directed by proteins that interact with chromatin in a modification-sensitive manner. This highly complex system operates with a large number of chemical modifications on chromatin (both DNA and histones) and transcription-associated proteins.1 Of these, lysine acetylation functions to facilitate chromatin opening and productive transcriptional machinery assembly required for gene activation. These activities are directed by the acetyl-lysine binding activity of the Bromodomain (BrD), a fundamental molecular mechanism for gene transcriptional activation that was discovered in the structural biology study of the histone acetyltransferase (HAT) transcriptional co-activator PCAF.2 The human genome encodes a total of 61 Bromodomains in 46 chromatin regulator proteins, some of which comprise multiple Bromodomains.2 As a key epigenome reader, the Bromodomain is almost solely responsible for binding to acetylated-lysine in histones and transcription-associated proteins, thereby orchestrating gene transcription in chromatin in an ordered fashion.2 Recent studies show that pharmacological small molecule modulation of the acetyl-lysine binding activity of BrD proteins such as the BET (Bromodomain and Extra-Terminal domain) family protein BRD4 and the HAT co-activator CBP/p300 dictates gene transcription outcome in disease models3 such as multiple myeloma, lymphoma, acute myeloid leukemia, mixed lineage leukemia, HIV-associated kidney disease, and ischemia, indicating these Bromodomains as attractive drug targets for diseases including cancer and inflammation.
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Biochemical Profiling of Histone Binding Selectivity of the Yeast Bromodomain Family
PLOS ONE, 2010Co-Authors: Suvobrata Chakravarty, Dario Ghersi, Roberto Sanchez, Alexander N Plotnikov, Lei Zeng, Ming-ming ZhouAbstract:Background It has been shown that molecular interactions between site-specific chemical modifications such as acetylation and methylation on DNA-packing histones and conserved structural modules present in transcriptional proteins are closely associated with chromatin structural changes and gene activation. Unlike methyl-lysine that can interact with different protein modules including chromodomains, Tudor and MBT domains, as well as PHD fingers, acetyl-lysine (Kac) is known thus far to be recognized only by Bromodomains. While histone lysine acetylation plays a crucial role in regulation of chromatin-mediated gene transcription, a high degree of sequence variation of the acetyl-lysine binding site in the Bromodomains has limited our understanding of histone binding selectivity of the Bromodomain family. Here, we report a systematic family-wide analysis of 14 yeast Bromodomains binding to 32 lysine-acetylated peptides derived from known major acetylation sites in four core histones that are conserved in eukaryotes. Methodology The histone binding selectivity of purified recombinant yeast Bromodomains was assessed by using the native core histones in an overlay assay, as well as N-terminally biotinylated lysine-acetylated histone peptides spotted on streptavidin-coated nitrocellulose membrane in a dot blot assay. NMR binding analysis further validated the interactions between histones and selected Bromodomain. Structural models of all yeast Bromodomains were built using comparative modeling to provide insights into the molecular basis of their histone binding selectivity. Conclusions Our study reveals that while not all members of the Bromodomain family are privileged to interact with acetylated-lysine, identifiable sequence features from those that bind histone emerge. These include an asparagine residue at the C-terminus of the third helix in the 4-helix bundle, negatively charged residues around the ZA loop, and preponderance of aromatic amino acid residues in the binding pocket. Further, while Bromodomains exhibit selectivity for different sites in histones, individual interactions are of modest affinity. Finally, electrostatic interactions appear to be a primary determining factor that guides productive association between a Bromodomain and a lysine-acetylated histone.
Chunwa Chung - One of the best experts on this subject based on the ideXlab platform.
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Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second Bromodomain
Journal of medicinal chemistry, 2018Co-Authors: Robert P. Law, Chunwa Chung, Rab K. Prinjha, Stephen John Atkinson, Paul Bamborough, Emmanuel Hubert Demont, Laurie J. Gordon, Lindon Matthew J, Allan J. B. Watson, Hirst David JonathanAbstract:The Bromodomain and extra-terminal domain (BET) family of proteins bind acetylated lysine residues on histone proteins. The four BET Bromodomains—BRD2, BRD3, BRD4, and BRDT—each contain two Bromodomain modules. BET Bromodomain inhibition is a potential therapy for various cancers and immunoinflammatory diseases, but few reported inhibitors show selectivity within the BET family. Inhibitors with selectivity for the first or second Bromodomain are desired to aid investigation of the biological function of these domains. Focused library screening identified a series of tetrahydroquinoxalines with selectivity for the second Bromodomains of the BET family (BD2). Structure-guided optimization of the template improved potency, selectivity, and physicochemical properties, culminating in potent BET inhibitors with BD2 selectivity.
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Aiming to Miss a Moving Target: Bromo and Extra Terminal Domain (BET) Selectivity in Constrained ATAD2 Inhibitors
2018Co-Authors: Paul Bamborough, Chunwa Chung, Rab K. Prinjha, Rebecca C. Furze, Paola Grandi, Anne-marie Michon, Robert J. Watson, Darren J. Mitchell, Heather Barnett, Christina RauAbstract:ATAD2 is a cancer-associated protein whose Bromodomain has been described as among the least druggable of its class. In our recent disclosure of the first chemical probe against this Bromodomain, GSK8814 (6), we described the use of a conformationally constrained methoxy piperidine to gain selectivity over the BET Bromodomains. Here we describe an orthogonal conformational restriction strategy of the piperidine ring to give potent and selective tropane inhibitors and show structural insights into why this was more challenging than expected. Greater understanding of why different rational approaches succeeded or failed should help in the future design of selectivity in the Bromodomain family
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discovery of i brd9 a selective cell active chemical probe for Bromodomain containing protein 9 inhibition
Journal of Medicinal Chemistry, 2016Co-Authors: Natalie Hope Theodoulou, Chunwa Chung, Paul Bamborough, Andrew J Bannister, Isabelle Becher, Rino A Bit, Ka Hing Che, Antje Dittmann, Gerard Drewes, David H DrewryAbstract:Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by Bromodomain “reader” modules. Inhibitors of the Bromodomain and extra terminal domain (BET) family of Bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other Bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for Bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous Bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 Bromodomain ...
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Structure-Based Optimization of Naphthyridones into Potent ATAD2 Bromodomain Inhibitors.
Journal of medicinal chemistry, 2015Co-Authors: Paul Bamborough, Chunwa Chung, Rebecca C. Furze, Paola Grandi, Anne-marie Michon, Robert J. Sheppard, Heather Anne Barnett, Hawa Diallo, David P. Dixon, Clement DouaultAbstract:ATAD2 is a Bromodomain-containing protein whose overexpression is linked to poor outcomes in a number of different cancer types. To date, no potent and selective inhibitors of the Bromodomain have been reported. This article describes the structure-based optimization of a series of naphthyridones from micromolar leads with no selectivity over the BET Bromodomains to inhibitors with sub-100 nM ATAD2 potency and 100-fold BET selectivity.
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Naphthyridines as Novel Bet Family Bromodomain Inhibitors.
ChemMedChem, 2013Co-Authors: Olivier Mirguet, Chunwa Chung, Paul Bamborough, Yann Lamotte, Delphine Delannée, Anne Marie Jeanne Bouillot, Francoise Jeanne Gellibert, Gael Krysa, Antonia J. Lewis, Jason WitheringtonAbstract:Bromodomains (BRDs) are small protein domains found in a variety of proteins that recognize and bind to acetylated histone tails. This binding affects chromatin structure and facilitates the localisation of transcriptional complexes to specific genes, thereby regulating epigenetically controlled processes including gene transcription and mRNA elongation. Inhibitors of the Bromodomain and extra-terminal (BET) proteins BRD2-4 and T, which prevent Bromodomain binding to acetyl-modified histone tails, have shown therapeutic promise in several diseases. We report here the discovery of 1,5-naphthyridine derivatives as potent inhibitors of the BET Bromodomain family with good cell activity and oral pharmacokinetic parameters. X-ray crystal structures of naphthyridine isomers have been solved and quantum mechanical calculations have been used to explain the higher affinity of the 1,5-isomer over the others. The best compounds were progressed in a mouse model of inflammation and exhibited dose-dependent anti-inflammatory pharmacology.
Martin Philpott - One of the best experts on this subject based on the ideXlab platform.
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Bromodomain inhibition of the coactivators CBP/EP300 facilitate cellular reprogramming.
Nature chemical biology, 2019Co-Authors: Ayyub Ebrahimi, Kenan Sevinç, Gülben Gürhan Sevinç, Adam P. Cribbs, Martin Philpott, Fırat Uyulur, Tunc Morova, James E. Dunford, Sencer Göklemez, Şule ArıAbstract:Silencing of the somatic cell type-specific genes is a critical yet poorly understood step in reprogramming. To uncover pathways that maintain cell identity, we performed a reprogramming screen using inhibitors of chromatin factors. Here, we identify acetyl-lysine competitive inhibitors targeting the Bromodomains of coactivators CREB (cyclic-AMP response element binding protein) binding protein (CBP) and E1A binding protein of 300 kDa (EP300) as potent enhancers of reprogramming. These inhibitors accelerate reprogramming, are critical during its early stages and, when combined with DOT1L inhibition, enable efficient derivation of human induced pluripotent stem cells (iPSCs) with OCT4 and SOX2. In contrast, catalytic inhibition of CBP/EP300 prevents iPSC formation, suggesting distinct functions for different coactivator domains in reprogramming. CBP/EP300 Bromodomain inhibition decreases somatic-specific gene expression, histone H3 lysine 27 acetylation (H3K27Ac) and chromatin accessibility at target promoters and enhancers. The master mesenchymal transcription factor PRRX1 is one such functionally important target of CBP/EP300 Bromodomain inhibition. Collectively, these results show that CBP/EP300 Bromodomains sustain cell-type-specific gene expression and maintain cell identity. A chromatin-focused chemical screen identified CBP/EP300 Bromodomain inhibitors as enhancers of reprogramming. These inhibitors decrease histone H3 lysine 27 acetylation, chromatin accessibility and expression of somatic-specific genes.
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Bromodomain inhibition of the coactivators cbp ep300 facilitate cellular reprogramming
Nature Chemical Biology, 2019Co-Authors: Ayyub Ebrahimi, Kenan Sevinç, Gülben Gürhan Sevinç, Adam P. Cribbs, Martin Philpott, Fırat Uyulur, Tunc Morova, James E. DunfordAbstract:Silencing of the somatic cell type-specific genes is a critical yet poorly understood step in reprogramming. To uncover pathways that maintain cell identity, we performed a reprogramming screen using inhibitors of chromatin factors. Here, we identify acetyl-lysine competitive inhibitors targeting the Bromodomains of coactivators CREB (cyclic-AMP response element binding protein) binding protein (CBP) and E1A binding protein of 300 kDa (EP300) as potent enhancers of reprogramming. These inhibitors accelerate reprogramming, are critical during its early stages and, when combined with DOT1L inhibition, enable efficient derivation of human induced pluripotent stem cells (iPSCs) with OCT4 and SOX2. In contrast, catalytic inhibition of CBP/EP300 prevents iPSC formation, suggesting distinct functions for different coactivator domains in reprogramming. CBP/EP300 Bromodomain inhibition decreases somatic-specific gene expression, histone H3 lysine 27 acetylation (H3K27Ac) and chromatin accessibility at target promoters and enhancers. The master mesenchymal transcription factor PRRX1 is one such functionally important target of CBP/EP300 Bromodomain inhibition. Collectively, these results show that CBP/EP300 Bromodomains sustain cell-type-specific gene expression and maintain cell identity. A chromatin-focused chemical screen identified CBP/EP300 Bromodomain inhibitors as enhancers of reprogramming. These inhibitors decrease histone H3 lysine 27 acetylation, chromatin accessibility and expression of somatic-specific genes.
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[1,2,4]Triazolo[4,3‑a]phthalazines: Inhibitors of Diverse
2016Co-Authors: O Fedorov, Martin Philpott, Hannah Lingard, Octovia P Monteiro, S Picaud, T Keates, I Felletar, Chris Wells, Sarah J. Martin, Brian D. MarsdenAbstract: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. This new 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. The rapidly expanding field of epigenetics can be broadly divided into two levels of processes: DNA methylation and histone modification. Various post-translational modification
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Assessing cellular efficacy of Bromodomain inhibitors using fluorescence recovery after photobleaching.
Epigenetics & chromatin, 2014Co-Authors: Martin Philpott, Stefan Knapp, Clarence Yapp, Chris Wells, Catherine Rogers, Jean-philippe Lambert, Claire Strain-damerell, N.a. Burgess-brown, Anne-claude Gingras, Susanne MüllerAbstract:Acetylation of lysine residues in histone tails plays an important role in the regulation of gene transcription. Bromdomains are the readers of acetylated histone marks, and, consequently, Bromodomain-containing proteins have a variety of chromatin-related functions. Moreover, they are increasingly being recognised as important mediators of a wide range of diseases. The first potent and selective Bromodomain inhibitors are beginning to be described, but the diverse or unknown functions of Bromodomain-containing proteins present challenges to systematically demonstrating cellular efficacy and selectivity for these inhibitors. Here we assess the viability of fluorescence recovery after photobleaching (FRAP) assays as a target agnostic method for the direct visualisation of an on-target effect of Bromodomain inhibitors in living cells. Mutation of a conserved asparagine crucial for binding to acetylated lysines in the Bromodomains of BRD3, BRD4 and TRIM24 all resulted in reduction of FRAP recovery times, indicating loss of or significantly reduced binding to acetylated chromatin, as did the addition of known inhibitors. Significant differences between wild type and Bromodomain mutants for ATAD2, BAZ2A, BRD1, BRD7, GCN5L2, SMARCA2 and ZMYND11 required the addition of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) to amplify the binding contribution of the Bromodomain. Under these conditions, known inhibitors decreased FRAP recovery times back to mutant control levels. Mutation of the Bromodomain did not alter FRAP recovery times for full-length CREBBP, even in the presence of SAHA, indicating that other domains are primarily responsible for anchoring CREBBP to chromatin. However, FRAP assays with multimerised CREBBP Bromodomains resulted in a good assay to assess the efficacy of Bromodomain inhibitors to this target. The Bromodomain and extraterminal protein inhibitor PFI-1 was inactive against other Bromodomain targets, demonstrating the specificity of the method. Viable FRAP assays were established for 11 representative Bromodomain-containing proteins that broadly cover the Bromodomain phylogenetic tree. Addition of SAHA can overcome weak binding to chromatin, and the use of tandem Bromodomain constructs can eliminate masking effects of other chromatin binding domains. Together, these results demonstrate that FRAP assays offer a potentially pan-Bromodomain method for generating cell-based assays, allowing the testing of compounds with respect to cell permeability, on-target efficacy and selectivity.
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discovery and optimization of small molecule ligands for the cbp p300 Bromodomains
Journal of the American Chemical Society, 2014Co-Authors: Duncan Hay, O Fedorov, Martin Philpott, Christopher Wells, S Picaud, Sarah Martin, C Tallant, Dean C Singleton, Octovia Monteiro, Catherine RogersAbstract: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.
O Fedorov - One of the best experts on this subject based on the ideXlab platform.
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[1,2,4]Triazolo[4,3‑a]phthalazines: Inhibitors of Diverse
2016Co-Authors: O Fedorov, Martin Philpott, Hannah Lingard, Octovia P Monteiro, S Picaud, T Keates, I Felletar, Chris Wells, Sarah J. Martin, Brian D. MarsdenAbstract: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. This new 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. The rapidly expanding field of epigenetics can be broadly divided into two levels of processes: DNA methylation and histone modification. Various post-translational modification
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cbp30 a selective cbp p300 Bromodomain inhibitor suppresses human th17 responses
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: A Hammitzsch, O Fedorov, C Tallant, Alison Omahony, Paul Brennan, Duncan Hay, Fernando O Martinez, Hussein Almossawi, Jelle De Wit, Matteo VecellioAbstract: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.
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discovery and optimization of small molecule ligands for the cbp p300 Bromodomains
Journal of the American Chemical Society, 2014Co-Authors: Duncan Hay, O Fedorov, Martin Philpott, Christopher Wells, S Picaud, Sarah Martin, C Tallant, Dean C Singleton, Octovia Monteiro, Catherine RogersAbstract: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.
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1 2 4 triazolo 4 3 a phthalazines inhibitors of diverse Bromodomains
Journal of Medicinal Chemistry, 2014Co-Authors: O Fedorov, Martin Philpott, Hannah Lingard, Christopher Wells, Octovia P Monteiro, S Picaud, T Keates, Clarence Yapp, Sarah Martin, I FelletarAbstract: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. This new 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.
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targeting low druggability Bromodomains fragment based screening and inhibitor design against the baz2b Bromodomain
Journal of Medicinal Chemistry, 2013Co-Authors: Fleur M Ferguson, O Fedorov, S Knapp, Martin Philpott, I Felletar, A Chaikuad, J R C Muniz, Frank Von Delft, Tom D Heightman, Chris AbellAbstract:Bromodomains are epigenetic reader domains that have recently become popular targets. In contrast to BET Bromodomains, which have proven druggable, Bromodomains from other regions of the phylogenetic tree have shallower pockets. We describe successful targeting of the challenging BAZ2B Bromodomain using biophysical fragment screening and structure-based optimization of high ligand-efficiency fragments into a novel series of low-micromolar inhibitors. Our results provide attractive leads for development of BAZ2B chemical probes and indicate the whole family may be tractable.
Paul Bamborough - One of the best experts on this subject based on the ideXlab platform.
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Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second Bromodomain
Journal of medicinal chemistry, 2018Co-Authors: Robert P. Law, Chunwa Chung, Rab K. Prinjha, Stephen John Atkinson, Paul Bamborough, Emmanuel Hubert Demont, Laurie J. Gordon, Lindon Matthew J, Allan J. B. Watson, Hirst David JonathanAbstract:The Bromodomain and extra-terminal domain (BET) family of proteins bind acetylated lysine residues on histone proteins. The four BET Bromodomains—BRD2, BRD3, BRD4, and BRDT—each contain two Bromodomain modules. BET Bromodomain inhibition is a potential therapy for various cancers and immunoinflammatory diseases, but few reported inhibitors show selectivity within the BET family. Inhibitors with selectivity for the first or second Bromodomain are desired to aid investigation of the biological function of these domains. Focused library screening identified a series of tetrahydroquinoxalines with selectivity for the second Bromodomains of the BET family (BD2). Structure-guided optimization of the template improved potency, selectivity, and physicochemical properties, culminating in potent BET inhibitors with BD2 selectivity.
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Aiming to Miss a Moving Target: Bromo and Extra Terminal Domain (BET) Selectivity in Constrained ATAD2 Inhibitors
2018Co-Authors: Paul Bamborough, Chunwa Chung, Rab K. Prinjha, Rebecca C. Furze, Paola Grandi, Anne-marie Michon, Robert J. Watson, Darren J. Mitchell, Heather Barnett, Christina RauAbstract:ATAD2 is a cancer-associated protein whose Bromodomain has been described as among the least druggable of its class. In our recent disclosure of the first chemical probe against this Bromodomain, GSK8814 (6), we described the use of a conformationally constrained methoxy piperidine to gain selectivity over the BET Bromodomains. Here we describe an orthogonal conformational restriction strategy of the piperidine ring to give potent and selective tropane inhibitors and show structural insights into why this was more challenging than expected. Greater understanding of why different rational approaches succeeded or failed should help in the future design of selectivity in the Bromodomain family
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discovery of i brd9 a selective cell active chemical probe for Bromodomain containing protein 9 inhibition
Journal of Medicinal Chemistry, 2016Co-Authors: Natalie Hope Theodoulou, Chunwa Chung, Paul Bamborough, Andrew J Bannister, Isabelle Becher, Rino A Bit, Ka Hing Che, Antje Dittmann, Gerard Drewes, David H DrewryAbstract:Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by Bromodomain “reader” modules. Inhibitors of the Bromodomain and extra terminal domain (BET) family of Bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other Bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for Bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous Bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 Bromodomain ...
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Structure-Based Optimization of Naphthyridones into Potent ATAD2 Bromodomain Inhibitors.
Journal of medicinal chemistry, 2015Co-Authors: Paul Bamborough, Chunwa Chung, Rebecca C. Furze, Paola Grandi, Anne-marie Michon, Robert J. Sheppard, Heather Anne Barnett, Hawa Diallo, David P. Dixon, Clement DouaultAbstract:ATAD2 is a Bromodomain-containing protein whose overexpression is linked to poor outcomes in a number of different cancer types. To date, no potent and selective inhibitors of the Bromodomain have been reported. This article describes the structure-based optimization of a series of naphthyridones from micromolar leads with no selectivity over the BET Bromodomains to inhibitors with sub-100 nM ATAD2 potency and 100-fold BET selectivity.
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Naphthyridines as Novel Bet Family Bromodomain Inhibitors.
ChemMedChem, 2013Co-Authors: Olivier Mirguet, Chunwa Chung, Paul Bamborough, Yann Lamotte, Delphine Delannée, Anne Marie Jeanne Bouillot, Francoise Jeanne Gellibert, Gael Krysa, Antonia J. Lewis, Jason WitheringtonAbstract:Bromodomains (BRDs) are small protein domains found in a variety of proteins that recognize and bind to acetylated histone tails. This binding affects chromatin structure and facilitates the localisation of transcriptional complexes to specific genes, thereby regulating epigenetically controlled processes including gene transcription and mRNA elongation. Inhibitors of the Bromodomain and extra-terminal (BET) proteins BRD2-4 and T, which prevent Bromodomain binding to acetyl-modified histone tails, have shown therapeutic promise in several diseases. We report here the discovery of 1,5-naphthyridine derivatives as potent inhibitors of the BET Bromodomain family with good cell activity and oral pharmacokinetic parameters. X-ray crystal structures of naphthyridine isomers have been solved and quantum mechanical calculations have been used to explain the higher affinity of the 1,5-isomer over the others. The best compounds were progressed in a mouse model of inflammation and exhibited dose-dependent anti-inflammatory pharmacology.
