Journal ArticleDOI
Discovery of a Highly Selective BET BD2 Inhibitor from a DNA-Encoded Library Technology Screening Hit.
Francesco Rianjongdee,Stephen John Atkinson,Chun-wa Chung,Paola Grandi,James Gray,Laura J. Kaushansky,Patricia F 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 Hubert Demont +17 more
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TLDR
In this paper, the authors 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.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.read more
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Journal ArticleDOI
Visible Light-Promoted Divergent Benzoheterocyclization from Aldehydes for DNA-Encoded Chemical Libraries.
TL;DR: A visible light-promoted divergent synthesis of on-DNA benzoheterocycles from aldehydes is presented, demonstrating the feasibility of this approach in DNA-encoded chemical library construction.
Journal ArticleDOI
Targeting Bromodomain-Selective Inhibitors of BET Proteins in Drug Discovery and Development.
Juncheng Chen,Pan Tang,Yuxi Wang,Jiaxing Wang,Chengcan Yang,Yang Li,Gaoxia Yang,Fengbo Wu,Jifa Zhang,Liang Ouyang +9 more
TL;DR: It is illustrated that some BET bromodomain (BET-BD1 or BET-BD2)-selective inhibitors have advantage over pan-inhibitors, including reduced toxicity concerns, and the methods for enhancing the selectivity and potency of these inhibitors based on their different modes of interactions.
Journal ArticleDOI
Progress in the development of domain selective inhibitors of the bromo and extra terminal domain family (BET) proteins.
TL;DR: In this paper, the authors summarized the recent progress in the development of BD1 and BD2 selective BET inhibitors, and provided the perspectives for future studies of BET inhibitors. But, their focus was on the N-terminal two tandem bromodomains of the BET family proteins.
Journal ArticleDOI
Structure-Based Discovery and Optimization of Furo[3,2-c]pyridin-4(5H)-one Derivatives as Potent and Second Bromodomain (BD2)-Selective Bromo and Extra Terminal Domain (BET) Inhibitors.
Junhua Li,Cheng Zhang,Hong Xu,Chao Wang,Ruibo Dong,Hui-Rong Shen,Xiaoxi Zhuang,Xiaoshan Chen,Qiu Li,Jibu Lu,Maofeng Zhang,Xishan Wu,Kerry M. Loomes,Yulai Zhou,Yan Zhang,Jinsong Liu,Yong Xu +16 more
TL;DR: Data indicate that 8l may serve as a new and valuable lead compound for the development of potential therapeutics against acute myeloid leukemia (AML) and furo[3,2-c]pyridin-4(5H)-one derivatives as novel BD2-selective BET inhibitors.
Journal ArticleDOI
Discovery of 2-((2-methylbenzyl)thio)-6-oxo-4-(3,4,5-trimethoxyphenyl)-1,6-dihydropyrimidine-5-carbonitrile as a novel and effective bromodomain and extra-terminal (BET) inhibitor for the treatment of sepsis.
Xue Ming Chen,Fan-Cui Meng,Jingtian Zhang,Zijian Zhang,Xuan Ye,Weikun Zhang,Yuanyuan Tong,Xinrui Ji,R Xu,Xiao-Li Xu,Qixiu You,Zheng-Yu Jiang +11 more
TL;DR: In this article , a BRD4 inhibitor with a new scaffold, 27, was presented as a potential candidate for the treatment of sepsis, which decreased LPS-induced NO production and expression of the pro-inflammatory factors IL-6, IL-1β and TNF-α.
References
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Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening.
Carl A. Machutta,Christopher S. Kollmann,Kenneth E Lind,Xiaopeng Bai,Pan F. Chan,Jianzhong Huang,Lluis Ballell,Svetlana L. Belyanskaya,Gurdyal S. Besra,David Barros-Aguirre,Robert H. Bates,Paolo A. Centrella,Sandy S. Chang,Jing Chai,Anthony E. Choudhry,Aaron Coffin,Aaron Coffin,Christopher P. Davie,Hongfeng Deng,Jianghe Deng,Yun Ding,Jason W. Dodson,David T. Fosbenner,Enoch Gao,Taylor L. Graham,Todd L. Graybill,Karen A. Ingraham,Walter P. Johnson,Bryan W. King,Christopher R. Kwiatkowski,Joël Lelièvre,Yue Li,Xiaorong Liu,Quinn Lu,Ruth Lehr,Alfonso Mendoza-Losana,John D. Martin,Lynn McCloskey,Patti McCormick,Heather O’Keefe,Thomas O’Keeffe,Christina S. Pao,Christina S. Pao,Christopher B. Phelps,Hongwei Qi,Keith Rafferty,Genaro S. Scavello,Matt S. Steiginga,Flora S. Sundersingh,Sharon Sweitzer,Lawrence M. Szewczuk,Lawrence M. Szewczuk,Amy N. Taylor,May Fern Toh,Juan Wang,Minghui Wang,Devan J. Wilkins,Devan J. Wilkins,Bing Xia,Gang Yao,Jean Zhang,Jingye Zhou,Jingye Zhou,Christine Patricia Donahue,Jeffrey A. Messer,David J. Holmes,Christopher C. Arico-Muendel,Andrew J. Pope,Jeffrey W. Gross,Ghotas Evindar +69 more
TL;DR: The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.
Journal ArticleDOI
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,Robert E. Davis,Laurie J. Gordon,Paola Grandi,Massimo Petretich,Alex Phillipou,Rab K. Prinjha,Inmaculada Rioja,Peter Ernest Soden,Thilo Werner,Emmanuel Hubert Demont +13 more
TL;DR: 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 of proteins is disclosed.
Journal ArticleDOI
DNA-Encoded Library Technology-Based Discovery, Lead Optimization, and Prodrug Strategy toward Structurally Unique Indoleamine 2,3-Dioxygenase-1 (IDO1) Inhibitors.
Wieslaw M. Kazmierski,Bing Xia,John F. Miller,Martha Alicia De La Rosa,David Favre,Richard M. Dunham,Yoshiaki Washio,Zhengrong Zhu,Feng Wang,Makda Mebrahtu,Hongfeng Deng,Jonathan B. Basilla,Liping Wang,Ghotas Evindar,Lijun Fan,Alison Olszewski,Ninad V. Prabhu,Christopher P. Davie,Jeffrey A. Messer,Vicente Samano +19 more
TL;DR: The discovery of a novel IDO1 inhibitor class through the affinity selection of a previously-unreported indole-based DNA-encoded library (DEL) is reported, characterized by low-calculated human dose, best-in-class potential, and unusual inhibition mode by binding theIDO1 heme-free (apo) form.
Journal ArticleDOI
The Optimization of a Novel, Weak Bromo and Extra Terminal Domain (BET) Bromodomain Fragment Ligand to a Potent and Selective Second Bromodomain (BD2) Inhibitor
Jonathan Thomas Seal,Stephen John Atkinson,Aylott Helen Elizabeth,Paul Bamborough,Chun-wa Chung,Royston C. B. Copley,Laurie J. Gordon,Paola Grandi,James Gray,Lee Andrew Harrison,Thomas George Christopher Hayhow,Matthew J Lindon,Cassie Messenger,Anne-Marie Michon,Darren Jason Mitchell,Alex Preston,Rab K. Prinjha,Inmaculada Rioja,Simon Taylor,Ian D. Wall,Robert J. Watson,James Michael Woolven,Emmanuel Hubert Demont +22 more
TL;DR: The X-ray crystal structure-directed optimisation of a novel weak fragment ligand with a pan-second bromodomain (BD2) bias, to potent and highly BD2 selective inhibitors is described.
Journal ArticleDOI
Domain-selective targeting of BET proteins in cancer and immunological diseases.
TL;DR: Recent pharmacological approaches aimed at targeting a single or a subset of the eight bromodomains within the BET family which have the potential to tease apart clinical efficacy and safety signals of BET inhibitors are discussed.
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