抑制BET溴结构域作为癌症药物发现的治疗策略。
Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery.
作者信息
Fu Lei-lei, Tian Mao, Li Xiang, Li Jing-jing, Huang Jian, Ouyang Liang, Zhang Yonghui, Liu Bo
机构信息
State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, Department of Urology, West China Hospital, Sichuan University, Chengdu, China.
School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China.
出版信息
Oncotarget. 2015 Mar 20;6(8):5501-16. doi: 10.18632/oncotarget.3551.
As a conserved protein interaction module that recognizes and binds to acetylated lysine, bromodomain (BRD) contains a deep, largely hydrophobic acetyl lysine binding site. Proteins that share the feature of containing two BRDs and an extra-terminal domain belong to BET family, including BRD2, BRD3, BRD4 and BRDT. BET family proteins perform transcription regulatory function under normal conditions, while in cancer, they regulate transcription of several oncogenes, such as c-Myc and Bcl-2. Thus, targeting BET proteins may be a promising strategy, and intense interest of BET proteins has fueled the development of structure-based bromodomain inhibitors in cancer. In this review, we focus on summarizing several small-molecule BET inhibitors and their relevant anti-tumor mechanisms, which would provide a clue for exploiting new targeted BET inhibitors in the future cancer therapy.
作为一种识别并结合乙酰化赖氨酸的保守蛋白质相互作用模块，溴结构域（BRD）包含一个深的、主要为疏水的乙酰赖氨酸结合位点。具有两个BRD和一个额外末端结构域特征的蛋白质属于BET家族，包括BRD2、BRD3、BRD4和BRDT。BET家族蛋白在正常条件下执行转录调节功能，而在癌症中，它们调节多种癌基因的转录，如c-Myc和Bcl-2。因此，靶向BET蛋白可能是一种有前景的策略，对BET蛋白的浓厚兴趣推动了基于结构的溴结构域抑制剂在癌症治疗中的发展。在本综述中，我们着重总结几种小分子BET抑制剂及其相关的抗肿瘤机制，这将为未来癌症治疗中开发新的靶向BET抑制剂提供线索。
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