Bcl-2:从靶标到上市药物的研究进展

Bcl-2: research progress from target to launched drug

细胞凋亡对正常生命体的发育、维持内环境的稳态具有重要作用,而该过程的异常常常会引发机体病变。研究表明Bcl-2蛋白家族与细胞凋亡过程密切相关,而且也是治疗肿瘤的重要靶标。经过近20年的努力,已经发现了许多小分子Bcl-2抑制剂。特别是基于片段药物设计策略发现的小分子Bcl-2抑制剂venetoclax已于2016年被美国FDA批准上市。作为首个获批的基于蛋白-蛋白相互作用为靶点的小分子药物,venetoclax的研发综合运用了多种药物研发技术,在新药研发的历史中具有里程碑式的意义。本文主要对临床研究的Bcl-2抑制剂的研发历程进行简述。

Apoptosis is an important self-stabilizing mechanism of mulficellular organisms, which plays a vital role in the development of normal living organisms and the maintenance of tissue homeostasis. The abnormalities in apoptosis often lead to body lesions including tumors. Studies have shown that Bcl-2 protein with anti-apoptosis activity is an important target in the treatment of cancer. After nearly two decades of efforts, many small molecule Bcl-2 inhibitors have been discovered to induce cell apoptosis. The small-molecule Bcl-2 inhibitor, venetoclax, was developed based on fragment-based drug design strategy and approved by the FDA in 2016 for clinical application. This agent is the first approved small-molecule drug inhibiting Bcl-2 through protein-protein interaction to induce cell apoptosis. The achievement of venetoclax benefits from a combination of drug discovery technologies and represents a milestone in the history of drug discovery. In this review we will introduce the current progress in Bcl-2 inhibitors.