Journal of Medicinal Chemistry p. 1281 - 1297 (2015)
Update date:2022-08-15
Topics:
Zhao, Lele
Wang, Yingqing
Cao, Danyan
Chen, Tiantian
Wang, Qi
Li, Yanlian
Xu, Yechun
Zhang, Naixia
Wang, Xin
Chen, Danqi
Chen, Lin
Chen, Yue-Lei
Xia, Guangxin
Shi, Zhe
Liu, Yu-Chih
Lin, Yijyun
Miao, Zehong
Shen, Jingkang
Xiong, Bing
The signal transduction of acetylated histone can be processed through a recognition module, bromodomain. Several inhibitors targeting BRD4, one of the bromodomain members, are in clinical trials as anticancer drugs. Hereby, we report our efforts on discovery and optimization of a new series of 2-thiazolidinones as BRD4 inhibitors along our previous study. In this work, guided by crystal structure analysis, we reversed the sulfonamide group and identified a new binding mode. A structure-activity relationship study on this new series led to several potent BRD4 inhibitors with IC50 of about 0.05-0.1 μM in FP binding assay and GI50 of 0.1-0.3 μM in cell based assays. To complete the lead-like assessment of this series, we further checked its effects on BRD4 downstream protein c-Myc, investigated its selectivity among five different bromodomain proteins, as well as the metabolic stability test, and reinforced the utility of 2-thiazolidinone scaffold as BET bromodomain inhibitors in novel anticancer drug development.
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