I04-Macromolecular Crystallography
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Romain
Gosmini
,
Van Loc
Nguyen
,
Jérôme
Toum
,
Christophe
Simon
,
Jean-Marie G.
Brusq
,
Gael
Krysa
,
Olivier
Mirguet
,
Alizon M.
Riou-Eymard
,
Eric V.
Boursier
,
Lionel
Trottet
,
Paul
Bamborough
,
Hugh
Clark
,
Chun-Wa
Chung
,
Leanne
Cutler
,
Emmanuel H.
Demont
,
Rejbinder
Kaur
,
Antonia J.
Lewis
,
Mark B.
Schilling
,
Peter E.
Soden
,
Simon
Taylor
Abstract: Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has led to great interest in the discovery of novel inhibitor classes. Here we describe the identification of a novel tetrahydroquinoline series through up-regulation of apolipoprotein A1 and the optimization into potent compounds active in murine models of septic shock and neuroblastoma. At the molecular level, these effects are produced by inhibition of BET bromodomains. X-ray crystallography reveals the interactions explaining the structure–activity relationships of binding. The resulting lead molecule, I-BET726, represents a new, potent, and selective class of tetrahydroquinoline-based BET inhibitors.
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Oct 2014
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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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I03-Macromolecular Crystallography
I04-Macromolecular Crystallography
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Emmanuel H.
Demont
,
Chun-Wa
Chung
,
Rebecca C.
Furze
,
Paola
Grandi
,
Anne-Marie
Michon
,
Chris
Wellaway
,
Nathalie
Barrett
,
Angela M.
Bridges
,
Peter D.
Craggs
,
Hawa
Diallo
,
David P.
Dixon
,
Clement
Douault
,
Amanda J.
Emmons
,
Emma J.
Jones
,
Bhumika V.
Karamshi
,
Kelly
Locke
,
Darren J.
Mitchell
,
Bernadette H.
Mouzon
,
Rab K.
Prinjha
,
Paul
Bamborough
Abstract: Overexpression of ATAD2 (ATPase family, AAA domain containing 2) has been linked to disease severity and progression in a wide range of cancers, and is implicated in the regulation of several drivers of cancer growth. Little is known of the dependence of these effects upon the ATAD2 bromodomain, which has been categorized as among the least tractable of its class. The absence of any potent, selective inhibitors limits clear understanding of the therapeutic potential of the bromodomain. Here, we describe the discovery of a hit from a fragment-based targeted array. Optimization of this produced the first known micromolar inhibitors of the ATAD2 bromodomain.
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Jul 2015
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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
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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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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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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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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
,
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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I02-Macromolecular Crystallography
I03-Macromolecular Crystallography
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Francesco
Rianjongdee
,
Stephen J.
Atkinson
,
Chun-Wa
Chung
,
Paola
Grandi
,
James R. J.
Gray
,
Laura J.
Kaushansky
,
Patricia
Medeiros
,
Cassie
Messenger
,
Alex
Phillipou
,
Alex
Preston
,
Rab K.
Prinjha
,
Inmaculada
Rioja
,
Alexander L.
Satz
,
Simon
Taylor
,
Ian D.
Wall
,
Robert J.
Watson
,
Gang
Yao
,
Emmanuel H.
Demont
Abstract: Second-generation bromodomain and extra terminal (BET) inhibitors, which selectively target one of the two bromodomains in the BET proteins, have begun to emerge in the literature. These inhibitors aim to help determine the roles and functions of each domain and assess whether they can demonstrate an improved safety profile in clinical settings compared to pan-BET inhibitors. Herein, we describe the discovery of a novel BET BD2-selective chemotype using a structure-based drug design from a hit identified by DNA-encoded library technologies, showing a structural differentiation from key previously reported greater than 100-fold BD2-selective chemotypes GSK620, GSK046, and ABBV-744. Following a structure-based hypothesis for the selectivity and optimization of the physicochemical properties of the series, we identified 60 (GSK040), an in vitro ready and in vivo capable BET BD2-inhibitor of unprecedented selectivity (5000-fold) against BET BD1, excellent selectivity against other bromodomains, and good physicochemical properties. This novel chemical probe can be added to the toolbox used in the advancement of epigenetics research.
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Jul 2021
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I02-Macromolecular Crystallography
I03-Macromolecular Crystallography
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Lee A.
Harrison
,
Stephen J.
Atkinson
,
Anna
Bassil
,
Chun-Wa
Chung
,
Paola
Grandi
,
James R. J.
Gray
,
Etienne
Levernier
,
Antonia
Lewis
,
David
Lugo
,
Cassie
Messenger
,
Anne-Marie
Michon
,
Darren J.
Mitchell
,
Alex
Preston
,
Rab K.
Prinjha
,
Inmaculada
Rioja
,
Jonathan T.
Seal
,
Simon
Taylor
,
Ian D.
Wall
,
Robert J.
Watson
,
James M.
Woolven
,
Emmanuel H.
Demont
Abstract: Domain-specific BET bromodomain ligands represent an attractive target for drug discovery with the potential to unlock the therapeutic benefits of antagonizing these proteins without eliciting the toxicological aspects seen with pan-BET inhibitors. While we have reported several distinct classes of BD2 selective compounds, namely, GSK620, GSK549, and GSK046, only GSK046 shows high aqueous solubility. Herein, we describe the lead optimization of a further class of highly soluble compounds based upon a picolinamide chemotype. Focusing on achieving >1000-fold selectivity for BD2 over BD1 ,while retaining favorable physical chemical properties, compound 36 was identified as being 2000-fold selective for BD2 over BD1 (Brd4 data) with >1 mg/mL solubility in FaSSIF media. 36 represents a valuable new in vivo ready molecule for the exploration of the BD2 phenotype.
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Jul 2021
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