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
Drug Discovery and Design Center , State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica , Chinese Academy of Sciences , 555 Zuchongzhi Road , Shanghai 201203 , China . Email:
School of Life Science and Technology , ShanghaiTech University , 100 Haike Road , Shanghai 201210 , China.
Medchemcomm. 2017 Mar 17;8(6):1322-1331. doi: 10.1039/c7md00083a. eCollection 2017 Jun 1.
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.
作为溴结构域和额外末端结构域（BET）蛋白家族的一员，BRD4与癌症及其他疾病密切相关。小分子BRD4抑制剂已显示出在治疗BRD4相关癌症方面的潜在前景。在本研究中，我们报告了一类新型BRD4抑制剂的发现与评估，这类抑制剂共享一个三甲氧基环，并靶向人类BRD4蛋白的第一个溴结构域。最具活性的化合物DC-BD-03的IC值为2.01 μM。此外，还确定了化合物DC-BD-29与BRD4第一个溴结构域的高分辨率晶体结构，该结构揭示了结合模式并有助于进一步基于结构的优化。这些化合物在人白血病MV4-11细胞中表现出抗增殖活性，导致细胞周期停滞并诱导凋亡。因此，本研究结果表明这一系列化合物作为BRD4相关癌症治疗候选药物的潜力。
