Medical Research Center, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, 610031, China.
Department of Laboratory Medicine, Xindu District People's Hospital, Chengdu, Sichuan, 610500, China.
Eur J Med Chem. 2024 Dec 5;279:116901. doi: 10.1016/j.ejmech.2024.116901. Epub 2024 Sep 27.
Proteolysis-targeting chimeras (PROTACs) is regarded as an emerging therapeutic strategy with unlimited potential because of its mechanism of inducing target protein degradation though harnessing ubiquitin-proteasome system (UPS). Recently, researchers are combining the advantages of PROTACs and dual-targeted drugs to explore some new types of dual PROTACs degraders. The utilization of dual PROTACs not only enhances the efficiency of selective degradation for two or more distinct proteins, but also facilitates synergistic interactions between target proteins to optimize therapeutic efficacy as well as overcome resistance. In this review, we briefly investigate the innovative strategies of dual degraders based on bivalent or trivalent "Y-type" PROTACs in recent years, outline their design principles, degradation effects, and anticancer activities. Moreover, their advantages and limitations compared with traditional PROTACs will be discussed and provide the outlook on the associated challenges. Meaningfully, the development and application of these dual-targeted PROTACs may point out new directions for replacing numerous combination regimens in the future.
蛋白水解靶向嵌合体（PROTACs）被认为是一种有前途的治疗策略，因为它利用泛素-蛋白酶体系统（UPS）诱导靶蛋白降解的机制。最近，研究人员结合了 PROTACs 和双靶药物的优势，探索了一些新型的双 PROTACs 降解剂。双 PROTACs 的利用不仅提高了对两个或更多不同蛋白质的选择性降解效率，而且促进了靶蛋白之间的协同相互作用，从而优化了治疗效果并克服了耐药性。在这篇综述中，我们简要探讨了近年来基于双价或三价“Y 型”PROTACs 的双降解剂的创新策略，概述了它们的设计原则、降解效果和抗癌活性。此外，还将讨论它们与传统 PROTACs 相比的优缺点，并对相关挑战进行展望。有意义的是，这些双靶向 PROTACs 的开发和应用可能为未来取代众多联合治疗方案指明新的方向。
