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12 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I04-1-Macromolecular Crystallography (fixed wavelength)	GSK789: a selective inhibitor of the first bromodomains (BD1) of the bromo and extra terminal domain (BET) proteins Robert J Watson , Paul Bamborough , Heather A. Barnett , Chun-Wa Chung , Rob Davis , Laurie J. Gordon , Paola Grandi , Massimo Petretich , Alex Phillipou , Rab K. Prinjha , Inmaculada Rioja , Peter Soden , Thilo Werner , Emmanuel H Demont Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c00614 Show Abstract ▼ Abstract: Pan-BET inhibitors interact equipotently with all eight bromodomains of the BET family of proteins. They have shown profound efficacy in-vitro and in-vivo in oncology and immuno-modulatory models and a number are currently in clinical trials where significant safety signals have been reported. It is therefore important to understand the functional contribution of each bromodomain to assess the opportunity to tease apart efficacy and toxicity. This article discloses the in-vitro and cellular activity profile of GSK789, a potent, cell permeable and highly selective inhibitor of the first bromodomains of the BET family.	Jul 2020
I03-Macromolecular Crystallography	Application of atypical acetyl-lysine methyl mimetics in the development of selective inhibitors of the bromodomain-containing protein 7 (BRD7)/bromodomain-containing protein 9 (BRD9) bromodomains Michael A. Clegg , Paul Bamborough , Chun-Wa Chung , Peter D. Craggs , Laurie Gordon , Paola Grandi , Melanie Leveridge , Matthew Lindon , Gemma M. Liwicki , Anne-Marie Michon , Judit Molnar , Inmaculada Rioja , Peter E. Soden , Natalie H. Theodoulou , Thilo Werner , Nicholas C. O. Tomkinson , Rab K. Prinjha , Philip G. Humphreys Journal Of Medicinal Chemistry 63, 5816 - 5840 DOI: 10.1021/acs.jmedchem.0c00075 Show Abstract ▼ Abstract: Non-BET bromodomain-containing proteins have become attractive targets for the development of novel therapeutics targeting epigenetic pathways. To help facilitate the target validation of this class of proteins, structurally diverse small-molecule ligands and methodologies to produce selective inhibitors in a predictable fashion are in high demand. Herein, we report the development and application of atypical acetyl-lysine (KAc) methyl mimetics to take advantage of the differential stability of conserved water molecules in the bromodomain binding site. Discovery of the n-butyl group as an atypical KAc methyl mimetic allowed generation of 31 (GSK6776) as a soluble, permeable, and selective BRD7/9 inhibitor from a pyridazinone template. The n-butyl group was then used to enhance the bromodomain selectivity of an existing BRD9 inhibitor and to transform pan-bromodomain inhibitors into BRD7/9 selective compounds. Finally, a solvent-exposed vector was defined from the pyridazinone template to enable bifunctional molecule synthesis, and affinity enrichment chemoproteomic experiments were used to confirm several of the endogenous protein partners of BRD7 and BRD9, which form part of the chromatin remodeling PBAF and BAF complexes, respectively.	Jun 2020
I04-Macromolecular Crystallography	Optimisation of potent ATAD2 and CECR2 bromodomain inhibitors with an atypical binding mode Simon Lucas , Stephen J. Atkinson , Paul Bamborough , Heather A. Barnett , Chun-Wa Chung , Laurie J. Gordon , Darren J. Mitchell , Alexander Phillipou , Rab K. Prinjha , Robert J. Sheppard , Nicholas C. O. Tomkinson , Robert J. Watson , Emmanuel H. Demont Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c00021 Show Abstract ▼ Abstract: Most bromodomain inhibitors mimic the interactions of the natural acetylated lysine (KAc) histone substrate through key interactions with conserved asparagine and tyrosine residues within the binding pocket. Herein we report the optimisation of a series of phenyl sulfonamides which exhibit a novel mode of binding to non-Bromodomain and Extra Terminal Domain (non-BET) bromodomains through displacement of a normally conserved network of four water molecules. Starting from an initial hit molecule we report its divergent optimisation towards the ATPase family AAA domain containing 2 (ATAD2) and Cats Eye Syndrome Chromosome Region, Candidate 2 (CECR2) domains. This work concludes with the identification of (R)-55 (GSK232), a highly selective, cellularly penetrant CECR2 inhibitor with excellent physicochemical properties.	Apr 2020
I03-Macromolecular Crystallography	Discovery of a bromodomain and extraterminal inhibitor with a low predicted human dose through synergistic use of encoded library technology and fragment screening Christopher R. Wellaway , Dominique Amans , Paul Bamborough , Heather Barnett , Rino A. Bit , Jack A. Brown , Neil R. Carlson , Chun-Wa Chung , Anthony W. J. Cooper , Peter D. Craggs , Robert P. Davis , Tony W. Dean , John P. Evans , Laurie Gordon , Isobel L. Harada , David J. Hirst , Philip G. Humphreys , Katherine L. Jones , Antonia J. Lewis , Matthew J. Lindon , Dave Lugo , Mahnoor Mahmood , Scott Mccleary , Patricia Medeiros , Darren J. Mitchell , Michael O’sullivan , Armelle Le Gall , Vipulkumar K. Patel , Chris Patten , Darren L. Poole , Rishi R. Shah , Jane E. Smith , Kayleigh A. J. Stafford , Pamela J. Thomas , Mythily Vimal , Ian D. Wall , Robert J. Watson , Natalie Wellaway , Gang Yao , Rab K. Prinjha Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b01670 Show Abstract ▼ Abstract: The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET–KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.	Jan 2020
I02-Macromolecular Crystallography	A qualified success: discovery of a new series of ATAD2 bromodomain inhibitors with a novel binding mode using high-throughput screening and hit qualification Paul Bamborough , Chun-Wa Chung , Emmanuel H. Demont , Angela M. Bridges , Peter D. Craggs , David P. Dixon , Peter Francis , Rebecca C. Furze , Paola Grandi , Emma J. Jones , Bhumika Karamshi , Kelly Locke , Simon C. C. Lucas , Anne-Marie Michon , Darren J. Mitchell , Peter Pogány , Rab K. Prinjha , Christina Rau , Ana Maria Roa , Andrew D. Roberts , Robert J. Sheppard , Robert J. Watson Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b00673 Show Abstract ▼ Abstract: The bromodomain of ATAD2 has proved to be one of the least-tractable proteins within this target class. Here, we describe the discovery of a new class of inhibitors by high-throughput screening and show how the difficulties encountered in establishing a screening triage capable of finding progressible hits were overcome by data-driven optimization. Despite the prevalence of nonspecific hits and an exceptionally low progressible hit rate (0.001%), our optimized hit qualification strategy employing orthogonal biophysical methods enabled us to identify a single active series. The compounds have a novel ATAD2 binding mode with noncanonical features including the displacement of all conserved water molecules within the active site and a halogen-bonding interaction. In addition to reporting this new series and preliminary structure–activity relationship, we demonstrate the value of diversity screening to complement the knowledge-based approach used in our previous ATAD2 work. We also exemplify tactics that can increase the chance of success when seeking new chemical starting points for novel and less-tractable targets.	Aug 2019
I02-Macromolecular Crystallography	Aiming to miss a moving target: bromo and extra terminal domain (BET) selectivity in constrained ATAD2 inhibitors Paul Bamborough , Chun-Wa Chung , Rebecca C. Furze , Paola Grandi , Anne-Marie Michon , Robert J. Watson , Darren J. Mitchell , Heather Barnett , Rab K. Prinjha , Christina Rau , Robert J. Sheppard , Thilo Werner , Emmanuel H. Demont Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.8b00862 Diamond Proposal Number(s): [12279] Show Abstract ▼ Abstract: 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.	Sep 2018
I03-Macromolecular Crystallography	Discovery of a Potent, Cell Penetrant, and Selective p300/CBP-Associated Factor (PCAF)/General Control Nonderepressible 5 (GCN5) Bromodomain Chemical Probe Philip G. Humphreys , Paul Bamborough , Chun-wa Chung , Peter D. Craggs , Laurie Gordon , Paola Grandi , Thomas G. Hayhow , Jameed Hussain , Katherine L. Jones , Matthew Lindon , Anne-marie Michon , Jessica F. Renaux , Colin J. Suckling , David F. Tough , Rab K. Prinjha Journal Of Medicinal Chemistry 60, 695 - 709 DOI: 10.1021/acs.jmedchem.6b01566 Diamond Proposal Number(s): [12279] Show Abstract ▼ Abstract: p300/CREB binding protein associated factor (PCAF/KAT2B) and general control nonderepressible 5 (GCN5/KAT2A) are multidomain proteins that have been implicated in retroviral infection, inflammation pathways, and cancer development. However, outside of viral replication, little is known about the dependence of these effects on the C-terminal bromodomain. Herein, we report GSK4027 as a chemical probe for the PCAF/GCN5 bromodomain, together with GSK4028 as an enantiomeric negative control. The probe was optimized from a weakly potent, nonselective pyridazinone hit to deliver high potency for the PCAF/GCN5 bromodomain, high solubility, cellular target engagement, and ≥18000-fold selectivity over the BET family, together with ≥70-fold selectivity over the wider bromodomain families.	Jan 2017
I03-Macromolecular Crystallography	Structure-Based Optimization of Naphthyridones into Potent ATAD2 Bromodomain Inhibitors Paul Bamborough , Chun-wa Chung , Rebecca C. Furze , Paola Grandi , Anne-marie Michon , Robert J. Sheppard , Heather Barnett , Hawa Diallo , David P. Dixon , Clement Douault , Emma J. Jones , Bhumika Karamshi , Darren J. Mitchell , Rab K. Prinjha , Christina Rau , Robert J. Watson , Thilo Werner , Emmanuel H. Demont Journal Of Medicinal Chemistry 58 (15), 6151 - 6178 DOI: 10.1021/acs.jmedchem.5b00773 PMID: 26230603 Open Access Show Abstract ▼ Abstract: 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.	Aug 2015
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	Discovery of I-BRD9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition Natalie H. Theodoulou , Paul Bamborough , Andrew J. Bannister , Isabelle Becher , Rino A. Bit , Ka Hing Che , Chun-wa Chung , Antje Dittmann , Gerard Drewes , David H. Drewry , Laurie Gordon , Paola Grandi , Melanie Leveridge , Matthew Lindon , Anne-marie Michon , Judit Molnar , Samuel C. Robson , Nicholas C. O. Tomkinson , Tony Kouzarides , Phillips G. Humphreys Journal Of Medicinal Chemistry 27 (8) DOI: 10.1021/acs.jmedchem.5b00256 PMID: 25856009 Open Access Show Abstract ▼ Abstract: 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 inhibition.	Apr 2015
I03-Macromolecular Crystallography	1,3-Dimethyl Benzimidazolones Are Potent, Selective Inhibitors of the BRPF1 Bromodomain Emmanuel H. Demont , Paul Bamborough , Chun-wa Chung , Peter D. Craggs , David Fallon , Laurie J. Gordon , Paola Grandi , Clare I. Hobbs , Jameed Hussain , Emma J. Jones , Armelle Le Gall , Anne-marie Michon , Darren J. Mitchell , Rab K. Prinjha , Andy D. Roberts , Robert J. Sheppard , Robert J. Watson Acs Medicinal Chemistry Letters 5 (11), 1190 - 1195 DOI: 10.1021/ml5002932 PMID: 25408830 Open Access Show Abstract ▼ Abstract: The BRPF (bromodomain and PHD finger-containing) protein family are important scaffolding proteins for assembly of MYST histone acetyltransferase complexes. Here, we report the discovery, binding mode, and structure–activity relationship (SAR) of the first potent, selective series of inhibitors of the BRPF1 bromodomain.	Nov 2014

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