Yu Chen, Qingfan Yang, Jinrun Xu, Liyao Tang, Yan Zhang, Fukuan Du, Yueshui Zhao, Xu Wu, Mingxing Li, Jing Shen, Ruilin Ding, Hongying Cao, Wanping Li, Xiaobing Li, Meijuan Chen, Zhigui Wu, Chi Hin Cho, Yu Du, Qinglian Wen, Zhangang Xiao
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引用次数: 6
摘要
蛋白水解靶向嵌合体(Proteolysis targeting chimera, PROTAC)是一种有效的靶向蛋白降解(targeted protein degradation, TPD)方法。异双功能PROTAC分子由E3连接酶配体组成，通过连接物与感兴趣蛋白(POI)共价连接。PROTAC可以通过劫持泛素-蛋白酶体降解系统(UPS)诱导蛋白质的泛素化蛋白酶体降解。该技术具有靶向范围广、细胞通透性好、组织特异性强、选择性高、口服生物利用度高、可控性好等优点。迄今为止，越来越多的靶向胃肠道癌症的PROTACs已被成功开发，并且在许多情况下，它们的poi已被验证为临床药物靶点。据我们所知，目前有15种针对不同靶点的PROTACs正在临床试验中进行测试，在不久的将来可能会有更多的PROTACs加入。为此，本文详细介绍PROTACs的作用机制、研究进展及其在临床试验中的应用，并对PROTACs在胃肠道肿瘤中的相关研究成果进行总结。最后，我们讨论了PROTAC在癌症治疗中的优势和潜在的挑战。
Proteolysis targeting chimera (PROTAC) presents a powerful strategy for targeted protein degradation (TPD). The heterobifunctional PROTAC molecule consists of an E3 ligase ligand covalently linked to a protein of interest (POI) via a linker. PROTAC can induce ubiquitinated proteasomal degradation of proteins by hijacking the ubiquitin-proteasome degradation system (UPS). This technique has the advantages of broad targeting profile, good cell permeability, tissue specificity, high selectivity, oral bioavailability, and controllability. To date, a growing number of PROTACs targeting gastrointestinal cancers have been successfully developed, and, in many cases, their POIs have been validated as clinical drug targets. To the best of our knowledge, 15 PROTACs against various targets are currently tested in clinical trials, and many more are likely to be added in the near future. Therefore, this paper details the mechanism, research progress, and application in clinical trials of PROTACs, and summarizes the research achievements related to PROTACs in gastrointestinal cancers. Finally, we discuss the advantages and potential challenges of PROTAC for cancer treatment.
期刊介绍：
Molecular Therapy — Oncolytics is an international, online-only, open access journal focusing on the development and clinical testing of viral, cellular, and other biological therapies targeting cancer.
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