PROTACs在肿瘤治疗领域的研究与应用

Research and application of PROTACs in the field of cancer therapy

蛋白水解靶向嵌合分子(protein proteolysis-targeting chimeras,PROTACs)是一种可以直接降解靶蛋白的双功能嵌合体。PROTACs通过中间连接链将靶蛋白与E3泛素连接酶结合的配体连接起来,继而泛素化修饰靶蛋白,从而使其进入蛋白酶体途径降解。根据PROTACs的作用机理,可以设计合成靶向降解调控肿瘤发生发展相关蛋白的PROTAC分子,从而达到治疗肿瘤的效果。目前,多个靶向肿瘤相关蛋白(BET蛋白、TBK1、CDK4/6以及AR、ER等)的PROTAC分子已在体外和体内实验中表现出良好的作用效果,有望研究开发成为肿瘤靶向药物。本文将对PROTACs的发展及其在肿瘤治疗领域的应用进行述评。

Protein proteolysis-targeting chimeras (PROTACs) is a bifunctional chimera that can directly degrade target molecules.PROTACs linked ligands that bind to target molecules and E3 ubiquitin ligase via an intermediate linker,and then ubiquitinated to modify and degrade target molecules through proteasome.Due to the mechanism of action of PROTACs,they can be used to design and synthesize PROTACs that regulate proteins related to tumor development,to achieve the effect of tumor treatment.Currently,PROTAC molecules targeting multiple cancer-related proteins (BET protein,TBK1,cdk4/6,AR and ER,etc.) have been shown to have good effects in vitro and in vivo experiments,and are expected to be a means for the development of clinical tumor targeted drugs.The development of PROTACs and its application in tumor therapy will be described in detail.