溴尿嘧啶
化学
表观遗传学
配体(生物化学)
BRD4
同源建模
立体化学
小分子
体内
计算生物学
组合化学
生物化学
酶
受体
遗传学
基因
生物
作者
Jonathan Seal,Sophie Atkinson,Helen E. Aylott,Paul Bamborough,Chun‐wa Chung,Royston C. B. Copley,Laurie J. Gordon,Paola Grandi,James R. Gray,Lee A. Harrison,Thomas G. Hayhow,Matthew Lindon,Cassie Messenger,Anne-Marie Michon,Darren J. Mitchell,Alex Preston,Rab K. Prinjha,Inmaculada Rioja,S. Taylor,Ian D. Wall,Robert J. Watson,James M. Woolven,Emmanuel H. Demont
标识
DOI:10.1021/acs.jmedchem.0c00796
摘要
The profound efficacy, yet associated toxicity of pan-BET inhibitors is well documented. The possibility of an ameliorated safety profile driven by significantly selective (>100-fold) inhibition of a subset of the eight bromodomains is enticing, but challenging given the close homology. Herein, we describe the X-ray crystal structure-directed optimization of a novel weak fragment ligand with a pan-second bromodomain (BD2) bias, to potent and highly BD2 selective inhibitors. A template hopping approach, enabled by our parallel research into an orthogonal template (15, GSK046), was the basis for the high selectivity observed. This culminated in two tool molecules, 20 (GSK620) and 56 (GSK549), which showed an anti-inflammatory phenotype in human whole blood, confirming their cellular target engagement. Excellent broad selectivity, developability, and in vivo oral pharmacokinetics characterize these tools, which we hope will be of broad utility to the field of epigenetics research.
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