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

文献类型：期刊论文

作者Chen, Deheng3,4; Lu, Tian1,3; Yan, Ziqin3; Lu, Wenchao3,4; Lyu, Xilin3; Xu, Biling2,3; Jiang, Hualiang3; Chen, Kaixian1,3; Luo, Cheng1,3; Zhao, Yujun3,4
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2019-11-15
卷号182页码:21
关键词Bromodomain BET protein BD2 Selective Crystal structure
ISSN号0223-5234
DOI10.1016/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.
WOS关键词SMALL-MOLECULE INHIBITORS ; ACUTE-LEUKEMIA ; HOLE APPROACH ; POTENT ; BRD4 ; DESIGN ; OPTIMIZATION ; RECOGNITION ; DERIVATIVES ; BREAST
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研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000496896600050
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/282012]  
专题新药研究国家重点实验室
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.

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来源：上海药物研究所

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