School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China.
J Med Chem. 2021 Aug 12;64(15):10606-10620. doi: 10.1021/acs.jmedchem.1c00895. Epub 2021 Jul 28.
Targeted protein degradation is a promising area in the discovery and development of innovative therapeutics. Molecular glues mediate proximity-induced protein degradation and have intrinsic advantages over heterobifunctional proteolysis-targeting chimeras, including unprecedented mechanisms, distinct biological activities, and favorable physicochemical properties. Classical molecular glue degraders have been identified serendipitously, but rational discovery and design strategies are emerging rapidly. In this review, we aim to highlight the recent advances in molecular glues for targeted protein degradation and discuss the challenges in developing molecular glues into therapeutic agents. In particular, discovery strategies, action mechanisms, and representative case studies will be addressed.
靶向蛋白降解是创新治疗药物发现和开发的一个有前途的领域。分子胶水介导临近诱导的蛋白降解，与异双功能蛋白水解靶向嵌合体相比具有内在优势，包括前所未有的机制、独特的生物学活性和有利的物理化学性质。经典的分子胶水降解剂是偶然发现的，但合理的发现和设计策略正在迅速涌现。在这篇综述中，我们旨在强调靶向蛋白降解的分子胶水的最新进展，并讨论将分子胶水开发成治疗药物所面临的挑战。特别地，将讨论发现策略、作用机制和代表性案例研究。
