Key Laboratory of Theoretical Organic Chemistry & Functional Molecule, Ministry of Education, Hunan Provincial Key Laboratory of Controllable Preparation & Functional Application of Fine Polymers, School of Chemistry & Chemical Engineering, Hunan University of Science & Technology, Xiangtan, Hunan, 411201, PR China.
School of Pharmaceutical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, 271000, PR China.
Future Med Chem. 2020 May;12(10):915-938. doi: 10.4155/fmc-2019-0340. Epub 2020 Apr 9.
Proteolysis-targeting chimera (PROTAC) is a new technology to selectively degrade target proteins via ubiquitin-proteasome system. PROTAC molecules (PROTACs) are a class of heterobifunctional molecules, which contain a ligand targeting the protein of interest, a ligand recruiting an E3 ligase and a linker connecting these two ligands. They provide several advantages over traditional inhibitors in potency, selectivity and drug resistance. Thus, many promising PROTACs have been developed in the recent two decades, especially small-molecule PROTACs. In this review, we briefly introduce the mechanism of PROTACs and focus on the progress of small-molecule PROTACs based on different E3 ligases. In addition, we also introduce the opportunities and challenges of small-molecule PROTACs for cancer therapy.
蛋白水解靶向嵌合体（PROTAC）是一种通过泛素-蛋白酶体系统选择性降解靶蛋白的新技术。PROTAC 分子（PROTACs）是一类双功能杂合分子，包含一个靶向感兴趣蛋白的配体、一个招募 E3 连接酶的配体和连接这两个配体的连接子。与传统抑制剂相比，它们在效力、选择性和耐药性方面具有多项优势。因此，在过去的二十年中，已经开发出了许多有前途的 PROTACs，尤其是小分子 PROTACs。在这篇综述中，我们简要介绍了 PROTAC 的作用机制，并重点介绍了基于不同 E3 连接酶的小分子 PROTAC 的研究进展。此外，我们还介绍了小分子 PROTAC 在癌症治疗方面的机遇和挑战。
