小分子Bcl-2抑制剂的研究与开发

Research and Development of Small-molecule Bcl-2 Inhibitors

综述细胞凋亡的主要机制、Bcl-xL蛋白结构以及各类小分子Bcl-2抑制剂的研究与开发。高水平表达Bcl-2家族抗凋亡蛋白(如Bcl-2、Bcl-xL等)可导致肿瘤细胞的凋亡过程受阻,并对传统放、化疗产生抵抗性,而下调过表达Bcl-2和Bcl-xL蛋白则可诱导肿瘤细胞凋亡,且逆转肿瘤细胞对治疗的抵抗性或耐药性。因此,作为潜在的癌症治疗策略,以Bcl-2家族蛋白为靶点的小分子抑制剂已成为当今研究热点,X-射线晶体衍射、核磁共振技术、小分子数据库和计算机辅助药物设计等技术也广泛应用于小分子Bcl-2抑制剂的开发。

The main mechanism of cell apoptosis, structure of Bcl-xL protein and research and development of varied small-molecule Bcl-2 inhibitors were reviewed. The high-level expression of Bcl-2 family anti-apoptotic proteins, such as Bcl-2 and Bcl-xL in tumor cells, could lead to the inhibition of apoptosis and resistance to routine radio- and chemo-therapy. Moreover, the down-regulation of overexpressed Bcl-2 and Bcl-xL proteins could induce tumor cell apoptosis and reverse the resistance to therapy. Therefore, the small-molecule inhibitors targeting these proteins as a potential strategy for cancer treatment have held the research spotlight, and X-ray crystal diffraction, NMR, small-molecular libraries and computeraided drug design have been widely used in the development of small-molecule Bcl-2 inhibitors.