College of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, 312000, China.
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China.
Eur J Med Chem. 2019 Jul 15;174:159-180. doi: 10.1016/j.ejmech.2019.04.036. Epub 2019 Apr 19.
Inhibitors and nucleic acid based techniques were two main approaches to interfere with protein signaling and respective cascade in the past. Until recently, a new class of small molecules named proteolysis-targeting chimeras (PROTACs) have emerged. Each contains a target warhead, a linker and an E3 ligand. These bifunctional molecules recruit E3 ligases and target specific proteins for degradation via the ubiquitin (Ub) proteasome system (UPS). The degradation provides several advantages over inhibition in potency, selectivity and drug resistance. Thus, a variety of small molecule PROTACs have been discovered so far. In this review, we summarize the biological mechanism, advantages and recent progress of PROTACs, trying to offer an outlook in development of drugs targeting degradation in future.
在过去，抑制剂和基于核酸的技术是干扰蛋白质信号及其级联反应的两种主要方法。直到最近，一类新的小分子药物——蛋白水解靶向嵌合体（PROTACs）出现了。每个 PROTAC 都包含一个靶头、一个连接子和一个 E3 配体。这些双功能分子通过泛素（Ub）蛋白酶体系统（UPS）招募 E3 连接酶，并将特定的靶蛋白降解。与抑制作用相比，降解在效力、选择性和耐药性方面具有多种优势。因此，迄今为止已经发现了多种小分子 PROTACs。在这篇综述中，我们总结了 PROTACs 的生物学机制、优势和最新进展，试图为未来靶向降解药物的开发提供展望。
