Y06014 is a selective BET inhibitor for the treatment of prostate cancer
Tian-bang Wu1,2,
Qiu-ping Xiang2,
Chao Wang2,3,
Chun Wu2,
Cheng Zhang2,
Mao-feng Zhang4,
Zhao-xuan Liu2,
Yan Zhang2,
Lin-jiu Xiao1,
Yong Xu2,5,6
1 College of Science, Key Laboratory of Rare-earth Chemistry and Applying of Liaoning Province, Shenyang University of Chemical Technology, Shenyang 110142, China
2 Guangdong Provincial Key Laboratory of Biocomputing, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China
3 University of Chinese Academy of Sciences, Beijing 100049, China
4 College of Pharmacy, Taizhou Polytechnic College, Taizhou 225300, China
5 Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510005, China
6 State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
Correspondence to: Yan Zhang: zhang_yan2012@gibh.ac.cn, Lin-jiu Xiao: x109@163.com, Yong Xu: xu_yong@gibh.ac.cn,
DOI: 10.1038/s41401-021-00614-7
Received: 23 November 2020
Accepted: 13 January 2021
Advance online: 2 March 2021
Abstract
Bromodomain and extra-terminal proteins (BETs) are potential targets for the therapeutic treatment of prostate cancer (PC). Herein, we report the design, the synthesis, and a structure−activity relationship study of 6-(3,5-dimethylisoxazol-4-yl)benzo[cd]indol-2 (1H)-one derivative as novel selective BET inhibitors. One representative compound, 19 (Y06014), bound to BRD4(1) in the low micromolar range and demonstrated high selectivity for BRD4(1) over other non-BET bromodomain-containing proteins. This molecule also potently inhibited cell growth, colony formation, and mRNA expression of AR-regulated genes in PC cell lines. Y06014 also shows stronger activity than the second-generation antiandrogen enzalutamide. Y06014 may serve as a new small molecule probe for further validation of BET as a molecular target for PC drug development.
Keywords:
prostate cancer; bromodomain inhibitor; BRD4; Y06014; androgen receptor
