溴尿嘧啶
化学
表观遗传学
计算生物学
药物发现
BET抑制剂
小分子
化学图书馆
组合化学
生物化学
基因
生物
作者
Francesco Rianjongdee,Sophie Atkinson,Chun‐wa Chung,Paola Grandi,James R. Gray,Laura J. Kaushansky,Patricia F Medeiros,Cassie Messenger,Alex Phillipou,Alex Preston,Rab K. Prinjha,Inmaculada Rioja,Alexander L. Satz,S. Taylor,Ian D. Wall,Robert J. Watson,Gang Yao,Emmanuel H. Demont
标识
DOI:10.1021/acs.jmedchem.1c00412
摘要
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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