B淋巴细胞瘤-2抑制剂的研究进展

Advances in the B cell lymphoma-2 inhibitors

B淋巴细胞瘤(B cell lymphoma,Bcl)-2基因主要表达于线粒体外膜,是凋亡信号转导通路中的主要调节因子,其异常表达与肿瘤的发生、发展密切相关。Bcl-2蛋白由Bcl-2基因编码而来,通过蛋白间相互作用调控细胞凋亡,已成为治疗慢性淋巴细胞白血病(chronic lymphocytic leukemia,CLL)的重要靶点。Bcl-2抑制剂大部分为小分子化合物,基于片段的药物设计方法模拟Bcl-2蛋白的BH3结构域,推动Bcl-2抑制剂的研发。目前已上市的Bcl-2靶向抑制剂维奈克拉(venetoclax)能够有效治疗CLL和小淋巴细胞性白血病,对B淋巴细胞恶性肿瘤表现出较好的临床疗效,其他已进入临床研究的Bcl-2抑制剂也显示出较好的开发前景。现对Bcl-2的作用机制作简要综述,并总结近年Bcl-2抑制剂的研究进展,为其进一步研发提供启示。

B cell lymphoma(Bcl)-2 gene is mainly expressed in the outer mitochondrial membrane.It is the major regulator in the apoptotic signaling pathway,and its aberrant expression is closely related to tumor development.Bcl-2 protein,encoded by Bcl-2 gene,regulates apoptosis through protein-protein interactions and has become an important target for the treatment of chronic lymphocytic leukemia(CLL).Most of the Bcl-2 inhibitors are small molecule compounds.Fragment-based drug design approaches that mimic the BH3 structural domain of the Bcl-2 protein have driven the development of Bcl-2 inhibitors.The currently marketed Bcl-2-targeted inhibitor drug venetoclax can effectively treat CLL and small lymphocytic leukemia,and shows better clinical efficacy in B-lymphocyte malignancies,and other Bcl-2 inhibitor drugs that have entered clinical studies also show better development prospects.This article reviewed the mechanism of Bcl-2,and summarized the research progress of Bcl-2 inhibitors in recent years,to provide insights for the further development of Bcl-2 inhibitors.