Discovery of novel trimethoxy-ring BRD4 bromodomain inhibitors: AlphaScreen assay, crystallography and cell-based assay

• Published in: MedChemComm 2017-06, Vol.8 (6), p.1322-1331
• Main Authors: Chen, Zhifeng, Zhang, Hao, Liu, Shien, Xie, Yiqian, Jiang, Hao, Lu, Wenchao, Xu, Heng, Yue, Liyan, Zhang, Yuanyuan, Ding, Hong, Zheng, Mingyue, Yu, Kunqian, Chen, Kaixian, Jiang, Hualiang, Luo, Cheng
• Format: Article
• Language: English
• ISSN: 2040-2503; 2040-2511
• DOI: 10.1039/c7md00083a

As a member of the bromodomain and extra terminal domain (BET) protein family, BRD4 is closely related to cancers and other diseases. Small-molecule BRD4 inhibitors have already demonstrated promising potential for the therapy of BRD4-related cancers. In this study, we report the discovery and evaluation of a novel category of BRD4 inhibitors, which share a trimethoxy ring and target the first bromodomain of the human BRD4 protein. The IC value of the most potent compound, DC-BD-03, is 2.01 μM. In addition, a high-resolution crystal structure of the compound DC-BD-29 with the first bromodomain of BRD4 was determined, which revealed the binding mode and facilitated further structure-based optimization. These compounds exhibited anti-proliferation activity, caused cell cycle arrest, and induced apoptosis in human leukemia MV4-11 cells. Thus, the results presented in this study indicated the potential of this series of compounds as drug candidates for the therapy of BRD4-related cancers.