Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins
Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins
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BY27 作为 BET 蛋白第二溴结构域选择性抑制剂的发现、结构洞察和生物活性
DOI：
10.1016/j.ejmech.2019.111633
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发表时间：
2019-11-15
影响因子：
6.7
通讯作者：
Zhao, Yujun
中科院分区：
文献类型：
--
作者：
Chen, Deheng;Lu, Tian;Zhao, Yujun
Recently, selective inhibition of BET BD2 is emerging as a promising strategy for drug discovery. Despite significant progress in this area, systematic studies of selective BET BD2 inhibitors are still few. In this study, we report the discovery of a potent and selective BET BD2 inhibitor BY27 (47). Our high resolution co-crystal structures of 47/BRD2 BD1 and BD2 showed that the triazole group of 47, water molecules, H433 and N429 in BRD2 BD2 established a water-bridged H-bonding network, which is responsible for the observed selectivities. DNA microarray analysis of HepG2 cells treated with 47 or OTX015 demonstrated the transcriptome impact differences between a BET BD2 selective inhibitor and a pan BET inhibitor. In a MV4-11 mouse xenograft model, 47 caused 67% of tumor growth inhibition and was less toxic than a pan BET inhibitor I at high doses. We conclude that the improved safety profile of selective BET BD2 inhibitors warrant future studies in BET associated diseases. (C) 2019 Elsevier Masson SAS. All rights reserved.
