The ubiquitin (Ub)–proteasome system (UPS) is the major machinery mediating specific protein turnover in eukaryotic cells. By ubiquitylating unwanted, damaged, or harmful proteins and driving their degradation, UPS is involved in many important cellular processes. Several new UPS-based technologies, including molecular glue degraders and PROTACs (proteolysis-targeting chimeras) to promote protein degradation, and DUBTACs (deubiquitinase-targeting chimeras) to increase protein stability, have been developed. By specifically inducing the interactions between different Ub ligases and targeted proteins that are not otherwise related, molecular glue degraders and PROTACs degrade targeted proteins the UPS; in contrast, by inducing the proximity of targeted proteins to deubiquitinases, DUBTACs are created to clear degradable poly-Ub chains to stabilize targeted proteins. In this review, we summarize the recent research progress in molecular glue degraders, PROTACs, and DUBTACs and their applications. We discuss immunomodulatory drugs, sulfonamides, cyclin-dependent kinase–targeting molecular glue degraders, and new development of PROTACs. We also introduce the principle of DUBTAC and its applications. Finally, we propose a few future directions of these three technologies related to targeted protein homeostasis.

中文翻译：

---

蛋白质泛素化和去泛素化在药物发现中的应用


泛素（Ub）-蛋白酶体系统（UPS）是介导真核细胞中特定蛋白质周转的主要机制。通过泛素化不需要的、受损的或有害的蛋白质并促进其降解，UPS 参与了许多重要的细胞过程。现已开发出几种基于 UPS 的新技术，包括分子胶降解剂和促进蛋白质降解的 PROTAC（蛋白水解靶向嵌合体），以及提高蛋白质稳定性的 DUBTAC（去泛素酶靶向嵌合体）。通过特异性诱导不同的 Ub 连接酶和原本不相关的目标蛋白之间的相互作用，分子胶降解剂和 PROTAC 可以降解 UPS 的目标蛋白；相比之下，通过诱导目标蛋白与去泛素酶接近，DUBTAC 可以清除可降解的多聚泛素链，从而稳定目标蛋白。本文综述了分子胶降解剂、PROTACs和DUBTACs及其应用的最新研究进展。我们讨论免疫调节药物、磺胺类药物、细胞周期蛋白依赖性激酶靶向分子胶降解剂以及 PROTAC 的新发展。我们还介绍了DUBTAC的原理及其应用。最后，我们提出了这三种与靶向蛋白质稳态相关的技术的一些未来方向。