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.
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We gratefully acknowledge financial support from the Chinese National Programs for Key Research and Development (grant 2019YFE0123700, 2016YFB0201701), the Key International Cooperation Projects of the Chinese Academy of Sciences (grant 154144KYSB20180044 and 154144KYSB20180063), the Chinese Academy of Sciences STS Program (grant KFJ-STS-QYZX-090), the National Natural Science Foundation of China (grant 81673357), the Natural Science Foundation of Guangdong province (grant 2015A030312014, 2019A1515110592), the State Key Laboratory of Respiratory Disease (grant SKLRD-Z-202018), Guangdong Provincial Key Laboratory of Biocomputing (grant 2016B030301007), Frontier Research Program of Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory, grant 2018GZR110105016), the Natural Science Foundation of Jiangsu Province (grant BK20190246) and the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (grant 19KJB350011). The authors also gratefully acknowledge support from the Guangzhou Branch of the Supercomputing Center of the Chinese Academy of Sciences.
The authors declare no competing interests.
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Wu, Tb., Xiang, Qp., Wang, C. et al. Y06014 is a selective BET inhibitor for the treatment of prostate cancer. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00614-7
- prostate cancer
- bromodomain inhibitor
- androgen receptor