Zhao Chunlong, Dekker Frank J
Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713AV Groningen, The Netherlands.
ACS Pharmacol Transl Sci. 2022 Aug 22;5(9):710-723. doi: 10.1021/acsptsci.2c00089. eCollection 2022 Sep 9.
Despite the success of drug discovery over the past decades, many potential drug targets still remain intractable for small molecule modulation. The development of proteolysis targeting chimeras (PROTACs) that trigger degradation of the target proteins provides a conceptually novel approach to address drug targets that remained previously elusive. Currently, the main challenge of PROTAC development is the identification of efficient, tissue- and cell-selective PROTAC molecules with good drug-likeness and favorable safety profiles. This review focuses on strategies to enhance the effectiveness and selectivity of PROTACs. We provide a comprehensive summary of recently reported PROTAC design strategies and discuss the advantages and disadvantages of these strategies. Future perspectives for PROTAC design will also be discussed.
尽管在过去几十年中药物研发取得了成功，但许多潜在的药物靶点仍难以通过小分子进行调控。靶向蛋白降解嵌合体（PROTAC）能够引发靶蛋白的降解，其发展为解决以前难以捉摸的药物靶点提供了一种概念上全新的方法。目前，PROTAC开发的主要挑战是鉴定出具有良好类药性质和有利安全性的高效、组织和细胞选择性的PROTAC分子。本综述聚焦于提高PROTAC有效性和选择性的策略。我们全面总结了最近报道的PROTAC设计策略，并讨论了这些策略的优缺点。还将探讨PROTAC设计的未来前景。
