溴尿嘧啶
表观遗传学
组蛋白
乙酰化
染色质
BRD4
小分子
药物发现
化学
癌症
计算生物学
癌症研究
生物化学
癌症治疗
可药性
生物
细胞生物学
癌细胞
化学生物学
BET抑制剂
基因
DNA
作者
Lu Feng,Guan Wang,Yi Chen,Gu He,Bo Liu,Jie Liu,Cheng-Ming Chiang,Liang Ouyang
摘要
Bromodomain-containing protein 4 (BRD4), as the most studied member of the bromodomain and extra-terminal (BET) family, is a chromatin reader protein interpreting epigenetic codes through binding to acetylated histones and non-histone proteins, thereby regulating diverse cellular processes including cell cycle, cell differentiation, and cell proliferation. As a promising drug target, BRD4 function is closely related to cancer, inflammation, cardiovascular disease, and liver fibrosis. Currently, clinical resistance to BET inhibitors has limited their applications but synergistic antitumor effects have been observed when used in combination with other tumor inhibitors targeting additional cellular components such as PLK1, HDAC, CDK, and PARP1. Therefore, designing dual-target inhibitors of BET bromodomains is a rational strategy in cancer treatment to increase potency and reduce drug resistance. This review summarizes the protein structures and biological functions of BRD4 and discusses recent advances of dual BET inhibitors from a medicinal chemistry perspective. We also discuss the current design and discovery strategies for dual BET inhibitors, providing insight into potential discovery of additional dual-target BET inhibitors.
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