溴结构域蛋白4 BD1和BD2选择性抑制剂的研究进展

Advances in Research on Selective BRD4 BD1/BRD4 BD2 Inhibitors

溴结构域蛋白4(BRD4)在组蛋白乙酰化修饰过程中发挥着重要的作用,与多种包括恶性肿瘤在内的疾病发生发展密切相关。目前,已有多个BRD4抑制剂进入临床研究阶段。因泛BRD4小分子抑制剂因其选择性差而导致的不良反应等问题,最终多数临床研究被终止。BRD4高选择性抑制剂靶向肿瘤等疾病已成为BRD4抑制剂开发的新趋势。对BRD4蛋白的结构和生物学功能进行研究,并对目前已经报道的选择性BRD4 BD1和BRD4 BD2抑制剂以及BRD4选择性抑制剂产生选择性的结构基础和独特的适应证进行综述,旨在加深对BRD4蛋白功能了解的同时,为后续BRD4高选择性抑制剂的设计和拓展研究奠定基础。

Bromodomain-containing protein 4(BRD4),which plays an important role in the process of histone acetylation modification,is closely related to the occurrence and development of a variety of diseases including cancer.Currently,plenty of BRD4inhibitors have entered clinical studies.The side-effects caused by poor selectivity of pan-BRD4 small molecule inhibitors have led to the termination of most clinical trials.Highly selective inhibitors of BRD4 targeting cancer have become a new trend in the development of BRD4 inhibitors.This article introduces the structure and biological function of BRD4 protein,reviews the selective BRD4 BD1/BRD4 BD2 inhibitors previously reported,and summarizes the structural basis and unique indications for the selectivity of BRD4selective inhibitors,aiming to deepen the understanding of BRD4 protein function and lay the foundation for the subsequent design and expansion of highly selective BRD4 inhibitors.