3511-47-5Relevant academic research and scientific papers
Fragment-based drug discovery of 2-thiazolidinones as BRD4 inhibitors: 2. Structure-based optimization
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
, p. 1281 - 1297 (2015/03/04)
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.
