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
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
Citations
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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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Journal ArticleDOI
Template-Hopping Approach Leads to Potent, Selective, and Highly Soluble Bromo and Extraterminal Domain (BET) Second Bromodomain (BD2) Inhibitors.
Aylott Helen Elizabeth,Stephen John Atkinson,Paul Bamborough,Anna K. Bassil,Chun-wa Chung,Laurie J. Gordon,Paola Grandi,James Gray,Lee Andrew Harrison,Thomas George Christopher Hayhow,Cassie Messenger,Darren Jason Mitchell,Alexander N Phillipou,Alex Preston,Rab K. Prinjha,Francesco Rianjongdee,Inmaculada Rioja,Jonathan Thomas Seal,Ian D. Wall,Robert J. Watson,James Michael Woolven,Emmanuel Hubert Demont +21 more
TL;DR: In this paper, the second bromodomain (BD2) was replaced with a heterocyclic ring to mitigate the genotoxicity risk of GSK046.
Journal ArticleDOI
The development of highly potent and selective small molecule correctors of Z α1-antitrypsin misfolding.
John Liddle,Andrew C. Pearce,Christopher C. Arico-Muendel,Svetlana L. Belyanskaya,Andrew Brewster,Murray J. B. Brown,Chun-wa Chung,Alexis Denis,Nerina Dodic,Anthony Dossang,Peter Eddershaw,Diana Klimaszewska,Imran Haq,Duncan S. Holmes,Alistair M. Jagger,Toral Jakhria,Emilie Jigorel,Ken Lind,Jeffrey A. Messer,Margaret Neu,Allison Olszewski,Riccardo Ronzoni,James E. Rowedder,Martin Rüdiger,Steve Skinner,Kathrine J. Smith,Lionel Trottet,Iain Uings,Zhengrong Zhu,James A. Irving,David A. Lomas +30 more
TL;DR: In this article, small molecules that bind and stabilise Z α 1-antitrypsin were identified via a DNA-encoded library screen and a subsequent structure based optimisation led to a series of highly potent, selective and cellular active α1-antitripsin correctors.
Journal ArticleDOI
Discovery of 2,4-1H-Imidazole Carboxamides as Potent and Selective TAK1 Inhibitors.
Johan J. N. Veerman,Yorik B. Bruseker,Eddy Damen,Erik H. Heijne,Wendy van Bruggen,Koen F. W. Hekking,Rob Winkel,Christopher D. Hupp,Anthony D. Keefe,Julie Liu,Heather A. Thomson,Ying Zhang,John W. Cuozzo,Andrew J. McRiner,Mark J. Mulvihill,Peter van Rijnsbergen,Birgit Zech,Louis Renzetti,L. Babiss,Gerhard Müller +19 more
TL;DR: In this article, the authors reported the discovery of 2,4-1H-imidazole carboxamides as novel, biochemically potent and kinome selective inhibitors of transforming growth factor β-activated kinase 1 (TAK1).
Book ChapterDOI
Chapter 7:DNA-encoded Library Technology (ELT)
TL;DR: This chapter describes the synthesis, screening and practical applications of DELs for the identification of novel small-molecule leads for drug discovery and chemical biology probes.
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