溴结构域蛋白4小分子抑制剂及其降解剂的研究进展

Research Progress of Bromodomain-containing Protein 4 Small-Molecule Inhibitors and Its Degraders

溴结构域和超末端(BET)家族是一类能特异性识别乙酰化赖氨酸调控基因转录过程的蛋白,在多种疾病的发生发展中具有重要作用。溴结构域蛋白4(BRD4)是BET家族的一员,能够与乙酰化的组蛋白或非组蛋白结合,进而调节基因复制和转录,影响细胞周期、细胞分化、信号转导等过程。BRD4的表达上调与多种肿瘤的恶性发展密切相关,抑制或降解BRD4能有效控制肿瘤的恶性进展和远端转移。因此,BRD4是一个具有广阔前景的肿瘤表观遗传学靶标。近年来,BRD4的小分子抑制剂和降解剂受到了广泛的关注和研究,其单药或与其他抗肿瘤药物联合使用均表现出较好的抗肿瘤作用。通过对BRD4的结构特点、生物学功能、小分子抑制剂和降解剂的研究进展进行综述,以期为新型的BRD4抑制剂和降解剂的开发提供参考。

Bromodomain and extra-terminal(BET)family,a class of proteins that can specifically recognize acetylated lysine and regulate gene transcription,play an important role in the occurrence and development of diverse diseases.Bromodomain-containing protein 4(BRD4),a member of the BET family,can combine with acetylated histones or non-histones,thereby regulating gene replication and transcription,and affecting the cell cycle,cell differentiation and signal transduction.The up-regulation of BRD4 expression is closely related to the malignant development of various tumors.Inhibition or degradation of BRD4 can effectively control the malignant progression and distant metastasis of tumors.Therefore,BRD4 is a promising tumor epigenetic target.In recent years,small-molecule inhibitors and degraders for BRD4 have received extensive attention and research,and have shown good anti-tumor effects used either alone or in combination with other anti-tumor drugs.The structural characteristics,biological functions and research progress of small molecule inhibitors and degraders of BRD4 are reviewed,in order to provide reference for the development of new inhibitors and degraders of BRD4.