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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Journal ArticleDOI
Imiquimod-induced psoriasis-like skin inflammation is suppressed by BET bromodomain inhibitor in mice through RORC/IL-17A pathway modulation.
Ahmed Nadeem,Naif O. Al-Harbi,M. M. Al-Harbi,Ahmed M. El-Sherbeeny,Sheikh F. Ahmad,Nahid Siddiqui,Mushtaq A. Ansari,Khairy M.A. Zoheir,Sabry M. Attia,Khaled A. Al-Hosaini,Shakir D. Al-Sharary +10 more
TL;DR: The current study suggests that BET bromodomains are involved in psoriasis-like inflammation through induction of RORC/IL-17A pathway and inhibition of BET b romodomain may provide a new therapy against skin inflammation.
Journal ArticleDOI
Structure-Based Optimization of Naphthyridones into Potent ATAD2 Bromodomain Inhibitors.
Paul Bamborough,Chun-wa Chung,Rebecca C. Furze,Paola Grandi,Anne-Marie Michon,Robert J. Sheppard,Heather A. Barnett,Hawa Diallo,David P. Dixon,Clement Douault,Emma J. Jones,Bhumika Karamshi,Darren Jason Mitchell,Rab K. Prinjha,Christina Rau,Robert J. Watson,Thilo Werner,Emmanuel Hubert Demont +17 more
TL;DR: 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.
Journal ArticleDOI
Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second Bromodomain
Robert P. Law,Stephen John Atkinson,Paul Bamborough,Chun-wa Chung,Emmanuel Hubert Demont,Laurie J. Gordon,Matthew J Lindon,Rab K. Prinjha,Allan J. B. Watson,David Jonathan Hirst +9 more
TL;DR: Focused library screening identified a series of tetrahydroquinoxalines with selectivity for the second bromodomains of the BET family (BD2), culminating in potent BET inhibitors with BD2 selectivity.
Journal ArticleDOI
BET bromodomain inhibition suppresses transcriptional responses to cytokine-Jak-STAT signaling in a gene-specific manner in human monocytes.
Chun Hin Chan,Celestia Fang,Anna Yarilina,Rab K. Prinjha,Yu Qiao,Lionel B. Ivashkiv,Lionel B. Ivashkiv +6 more
TL;DR: The findings suggest that BET inhibition reduces inflammation partially through suppressing cytokine activity and expands the understanding of the inhibitory and potentially selective immunosuppressive effects of inhibiting BET proteins.
Journal ArticleDOI
5-Aryl-4-carboxamide-1,3-oxazoles: potent and selective GSK-3 inhibitors.
Gabriella Gentile,Giancarlo Merlo,Alfonso Pozzan,Giovanni Bernasconi,Benjamin D. Bax,Paul Bamborough,Angela Bridges,Paul S. Carter,Margarete Neu,Gang Yao,Caroline Brough,Geoffrey J. Cutler,Aaron Coffin,Svetlana L. Belyanskaya +13 more
TL;DR: 5-Aryl-4-carboxamide-1,3-oxazoles are a novel, potent and selective series of GSK-3 inhibitors and their optimization to yield compounds with cell activity and brain permeability is described.
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