肿瘤靶向抑制剂的PROTACs设计及在抗肿瘤新药开发中的应用

PROTACs’Design of Tumor-targeting Inhibitors and Their Use in the Development of New Anti-tumor Drugs

蛋白质的非正常表达往往会直接或间接导致癌症的发生。目前,靶向特定蛋白质的小分子抑制剂在肿瘤治疗领域中得到了广泛使用。然而,小分子抑制剂存在易使机体产生耐药性、靶蛋白范围有限及毒性较高等问题,限制了其临床应用。由此,蛋白质水解靶向嵌合体技术应运而生。蛋白质水解靶向嵌合体(proteolysis-targeting chimaeras,PROTACs)是一种人工合成的小分子化合物,由靶蛋白配体、连接体和E3泛素连接酶配体三部分组成。它可以利用人体自身的泛素-蛋白酶体系统(ubiquitin-proteasome system,UPS)使目标蛋白质泛素化并降解,在一定程度上解决了过度使用小分子抑制剂而产生耐药性的问题,且具有低毒性的优点。因此,综合我国发病率排名前五的癌症,总结在癌症领域利用已有小分子抑制剂开发的PROTACs的设计及应用,以期予以新药研究人员启发,扩展小分子靶向抑制剂的使用,突破难以成药位点的药物选择。

Abnormal protein expression often leads directly or indirectly to the development of cancer.Currently,small-molecule inhibitors that target specific proteins are widely used in tumor therapy.However,small-molecule inhibitors have problems such as susceptibility to drug resistance,limited range of target proteins,and high toxicity,which limit their clinical application.As a result,proteolysis-targeting chimaera technology has emerged.Proteolysis targeting chimaeras(PROTACs)are a type of synthetic small-molecule compound consisting of target protein ligand,linker and E3 ubiquitin ligase ligand.It can use the human body’s own ubiquitin-proteasome system(UPS)to ubiquitinate and degrade the target protein,which to some extent solves the problem of drug resistance caused by overuse of small-molecule inhibitors,and has the advantage of low toxicity.Therefore,this review has summarized the design and application of PROTACs developed by using existing small-molecule inhibitors in the field of cancer,based on the top five cancers with the highest incidence rate in China,with the aim of giving inspiration to new drug researchers,expanding the use of small-molecule targeted inhibitors,and breaking through the selection of drugs that are difficult to become drug sites.