Discovery of the First BRD4 Second Bromodomain (BD2)-Selective Inhibitors

被引：1

作者：

Li, Junhua ^{[1
]}

Hu, Qingqing ^{[1
]}

Zhu, Run ^{[1
,2
]}

Dong, Ruibo ^{[1
,3
]}

Shen, Hui ^{[1
]}

Hu, Jiankang ^{[1
]}

Zhang, Cheng ^{[1
]}

Zhang, Xiaohan ^{[4
]}

Xu, Tingting ^{[1
]}

Xiang, Qiuping ^{[5
]}

Zhang, Yan ^{[1
]}

Lin, Bin ^{[2
]}

Zhao, Linxiang ^{[2
]}

Wu, Xishan ^{[1
]}

Xu, Yong ^{[1
,2
]}

机构：

[1] Chinese Acad Sci, Inst Drug Discovery, Guangzhou Inst Biomed & Hlth, China New Zealand Joint Lab Biomed & Hlth,Guangdon, Guangzhou 510530, Peoples R China

[2] Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Peoples R China

[3] Jilin Univ, Sch Pharmaceut Sci, Changchun 130021, Jilin, Peoples R China

[4] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Anal & Testing Ctr, Guangzhou 510530, Peoples R China

[5] Guoke Ningbo Life Sci & Hlth Ind Res Inst, Ningbo 315010, Zhejiang, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 23期

基金：

国家重点研发计划; 中国国家自然科学基金; 中国博士后科学基金;

关键词：

HIGHLY SOLUBLE BROMO; SELECTIVE INHIBITORS; DOSE-ESCALATION; BET INHIBITORS; POTENT; BD2; PROTEINS; IDENTIFICATION; RVX-208; SERIES;

D O I：

10.1021/acs.jmedchem.4c02516

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Pan-BD2 inhibitors have been shown to retain an antileukemia effect and display less dose-limiting toxicities than pan-BET inhibitors. However, it is necessary to consider the potential off-target toxicity associated with the inhibition of four BET BD2 proteins. To date, no BRD4 BD2 domain selective inhibitor has been reported. Based on our previous pan-BD2 inhibitor 12 (XY153), we successfully identified 16o (XY221) as the first BRD4 BD2-selective inhibitor. 16o demonstrated potent binding affinity for BRD4 BD2 (IC50 = 5.8 nM), along with high pan-BD2 selectivity (667-fold over BRD4 BD1) and BRD4 BD2 domain selectivity (9-32-fold over BRD2/3/T BD2). The BRD4 BD2 selectivity of 16o was further confirmed by the BLI assay, showing 66-144-fold selectivity over other BET BD2 domains. 16o exhibited good liver microsomal stability (T-1/2 > 120 min) and pharmacokinetic properties (F = 13.1%). These data indicate that 16o may serve as a valuable candidate for BRD4 BD2 advancing epigenetic research.

引用

页码：21577 / 21616

页数：40

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