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31 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3, 4 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I02-Macromolecular Crystallography I03-Macromolecular Crystallography	Discovery of a highly selective BET BD2 inhibitor from a DNA-encoded library technology screening hit 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 Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c00412 Show Abstract ▼ 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.	Jul 2021
I02-Macromolecular Crystallography I03-Macromolecular Crystallography	Identification of a series of n-methylpyridine-2-carboxamides as potent and selective inhibitors of the second bromodomain (BD2) of the bromo and extra terminal domain (BET) proteins 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 Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c02155 Show Abstract ▼ 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.	Jul 2021
I02-Macromolecular Crystallography	Optimization of a series of 2,3-dihydrobenzofurans as highly potent, second bromodomain (BD2)-selective, bromo and extra-terminal domain (BET) inhibitors Simon C. C. Lucas , Stephen J. Atkinson , Chun-Wa Chung , Rob Davis , Laurie Gordon , Paola Grandi , James J. R. Gray , Thomas Grimes , Alexander Phillipou , Alex G. Preston , Rab K. Prinjha , Inmaculada Rioja , Simon Taylor , Nicholas C. O. Tomkinson , Ian Wall , Robert J. Watson , James Woolven , Emmanuel H. Demont Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c00344 Show Abstract ▼ Abstract: Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000-fold selectivity for the second bromodomain (BD2) over the first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised in vitro clearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor 71 (GSK852): a potent, 1000-fold-selective, highly soluble compound with good in vivo rat and dog pharmacokinetics.	Jul 2021
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	The development of highly potent and selective small molecule correctors of Z α1-antitrypsin misfolding John Liddle , Andrew C. Pearce , Christopher Arico-Muendel , Svetlana Belyanskaya , Andrew Brewster , Murray Brown , Chun-Wa Chung , Alexis Denis , Nerina Dodic , Anthony Dossang , Peter Eddershaw , Diana Klimaszewska , Imran Haq , Duncan S. Holmes , Alistair Jagger , Toral Jakhria , Emilie Jigorel , Ken Lind , Jeff Messer , Margaret Neu , Allison Olszewski , Riccardo Ronzoni , James Rowedder , Martin Rüdiger , Steve Skinner , Kathrine J. Smith , Lionel Trottet , Iain Uings , Zhengrong Zhu , James A. Irving , David A. Lomas Bioorganic & Medicinal Chemistry Letters 41 DOI: 10.1016/j.bmcl.2021.127973 Diamond Proposal Number(s): [23853, 17201] Show Abstract ▼ Abstract: α1-antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant α1-antitrypsin protein within the endoplasmic reticulum (ER) of hepatocytes. Small molecules that bind and stabilise Z α1-antitrypsin were identified via a DNA-encoded library screen. A subsequent structure based optimisation led to a series of highly potent, selective and cellular active α1-antitrypsin correctors.	Jun 2021
I03-Macromolecular Crystallography	Development of a small molecule that corrects misfolding and increases secretion of Z α 1 ‐antitrypsin David A. Lomas , James A. Irving , Christopher Arico‐muendel , Svetlana Belyanskaya , Andrew Brewster , Murray Brown , Chun‐wa Chung , Hitesh Dave , Alexis Denis , Nerina Dodic , Anthony Dossang , Peter Eddershaw , Diana Klimaszewska , Imran Haq , Duncan S Holmes , Jonathan P. Hutchinson , Alistair M. Jagger , Toral Jakhria , Emilie Jigorel , John Liddle , Ken Lind , Stefan J Marciniak , Jeff Messer , Margaret Neu , Allison Olszewski , Adriana Ordonez , Riccardo Ronzoni , James Rowedder , Martin Rüdiger , Steve Skinner , Kathrine J. Smith , Rebecca Terry , Lionel Trottet , Iain Uings , Steve Wilson , Zhengrong Zhu , Andrew C. Pearce Embo Molecular Medicine 13 DOI: 10.15252/emmm.202013167 Diamond Proposal Number(s): [23853] Open Access Show Abstract ▼ Abstract: Severe α1‐antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant α1‐antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA‐encoded chemical library to undertake a high‐throughput screen to identify small molecules that bind to, and stabilise Z α1‐antitrypsin. The lead compound blocks Z α1‐antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z α1‐antitrypsin threefold in an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerisation pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z α1‐antitrypsin into the plasma by sevenfold. There was no observable clearance of hepatic inclusions with respect to controls over the same time period. This study provides proof of principle that “mutation ameliorating” small molecules can block the aberrant polymerisation that underlies Z α1‐antitrypsin deficiency.	Mar 2021
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
I04-Macromolecular Crystallography	Design and development of a macrocyclic series targeting phosphoinositide 3-kinase δ Jonathan A. Spencer , Ian R. Baldwin , Nick Barton , Chun-Wa Chung , Máire A. Convery , Christopher D. Edwards , Craig Jamieson , David N. Mallett , James E. Rowedder , Paul Rowland , Daniel A. Thomas , Charlotte J. Hardy Acs Medicinal Chemistry Letters 11, 1386 - 1391 DOI: 10.1021/acsmedchemlett.0c00061 Show Abstract ▼ Abstract: A macrocyclization approach has been explored on a series of benzoxazine phosphoinositide 3-kinase δ inhibitors, resulting in compounds with improved potency, permeability, and in vivo clearance while maintaining good solubility. The thermodynamics of binding was explored via surface plasmon resonance, and the binding of lead macrocycle 19 was found to be almost exclusively entropically driven compared with progenitor 18, which demonstrated both enthalpic and entropic contributions. The pharmacokinetics of macrocycle 19 was also explored in vivo, where it showed reduced clearance when compared with the progenitor 18. This work adds to the growing body of evidence that macrocyclization could provide an alternative and complementary approach to the design of small-molecule inhibitors, with the potential to deliver differentiated properties.	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
I04-Macromolecular Crystallography	Exploring the SAR of the β-ketoacyl-ACP synthase inhibitor GSK3011724a and optimization around a genotoxic metabolite Fraser Cunningham , Jorge Esquivias , Raquel Fernández-Menéndez , Arancha Pérez , Ana Guardia , Jaime Escribano , Cristina Rivero , Mythily Vimal , Mónica Cacho , Paco De Dios-Antón , María Santos Martínez-Martínez , Elena Jiménez , Leticia Huertas Valentín , María José Rebollo-López , Eva María López-Román , Verónica Sousa-Morcuende , Joaquín Rullas , Margaret Neu , Chun-Wa Chung , Robert H. Bates Acs Infectious Diseases DOI: 10.1021/acsinfecdis.9b00493 Diamond Proposal Number(s): [5799] Show Abstract ▼ Abstract: In the course of optimizing a novel indazole sulfonamide series that inhibits β-ketoacyl-ACP synthase (KasA) of Mycobacterium tuberculosis, a mutagenic aniline metabolite was identified. Further lead optimization efforts were therefore dedicated to eliminating this critical liability by removing the embedded aniline moiety or modifying its steric or electronic environment. While the narrow SAR space against the target ultimately rendered this goal unsuccessful, key structural knowledge around the binding site of this underexplored target for TB was generated to inform future discovery efforts.	Mar 2020

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