Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins

doi:10.1016/j.ejmech.2019.111633

	Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins
	Chen, Deheng 3,4; Lu, Tian 1,3; Yan, Ziqin 3; Lu, Wenchao 3,4; Lyu, Xilin 3; Xu, Biling 2,3; Jiang, Hualiang 3; Chen, Kaixian 1,3; Luo, Cheng 1,3; Zhao, Yujun 3,4
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2019-11-15
卷号	182 页码:21
关键词	Bromodomain BET protein BD2 Selective Crystal structure
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2019.111633
通讯作者	Luo, Cheng(cluo@simm.ac.cn) ; Zhao, Yujun(yjzhao@simm.ac.cn)
英文摘要	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.
资助项目	National Natural Science Foundation of China[81872724] ; National Natural Science Foundation of China[81673295] ; National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81430084] ; National Natural Science Foundation of China[21820102008] ; Personalized medicines-molecular signature-based drug discovery and development, strategic priority research program of the Chinese Academy of Sciences[XDA12040329] ; K. C. Wong Education Foundation ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Science and Technology Commission of Shanghai Municipality[19XD1404700] ; National Science & Technology Major Project of China[2018ZX09711002]
WOS关键词	SMALL-MOLECULE INHIBITORS ; ACUTE-LEUKEMIA ; HOLE APPROACH ; POTENT ; BRD4 ; DESIGN ; OPTIMIZATION ; RECOGNITION ; DERIVATIVES ; BREAST
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000496896600050
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/282012]
专题	中国科学院上海药物研究所
通讯作者	Luo, Cheng; Zhao, Yujun
作者单位	1.Nanjing Univ Chinese Med, 138 Xianlin Rd, Nanjing 210023, Jiangsu, Peoples R China 2.Dalian Univ Technol, Sch Life Sci & Med, 2 Dagong Rd, Panjin, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Chen, Deheng,Lu, Tian,Yan, Ziqin,et al. Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2019,182:21.
APA	Chen, Deheng.,Lu, Tian.,Yan, Ziqin.,Lu, Wenchao.,Lyu, Xilin.,...&Zhao, Yujun.(2019).Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,182,21.
MLA	Chen, Deheng,et al."Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 182(2019):21.