I04-1-Macromolecular Crystallography (fixed wavelength)
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Robert J
Watson
,
Paul
Bamborough
,
Heather A.
Barnett
,
Chun-Wa
Chung
,
Rob
Davis
,
Laurie J.
Gordon
,
Paola
Grandi
,
Massimo
Petretich
,
Alex
Phillipou
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Rab K.
Prinjha
,
Inmaculada
Rioja
,
Peter
Soden
,
Thilo
Werner
,
Emmanuel H
Demont
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.
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Jul 2020
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I03-Macromolecular Crystallography
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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
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.
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Jun 2020
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I04-Macromolecular Crystallography
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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
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.
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Apr 2020
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I03-Macromolecular Crystallography
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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
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.
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Jan 2020
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I02-Macromolecular Crystallography
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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
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.
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Aug 2019
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I02-Macromolecular Crystallography
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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
Diamond Proposal Number(s):
[12279]
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.
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Sep 2018
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I03-Macromolecular Crystallography
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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
Diamond Proposal Number(s):
[12279]
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.
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Jan 2017
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I03-Macromolecular Crystallography
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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
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.
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Aug 2015
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I02-Macromolecular Crystallography
I04-Macromolecular Crystallography
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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
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.
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Apr 2015
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I03-Macromolecular Crystallography
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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
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.
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Nov 2014
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