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激酶分子胶:基于邻近诱导的蛋白-蛋白相互作用调控新策略

Kinase Molecular Glues: The New Strategy for Induced Proximiy of Protein–Protein Interactions

  • 摘要: 临近诱导策略以蛋白-蛋白相互作用(PPI)为核心,通过小分子介导靶蛋白与效应蛋白的空间邻近,触发泛素化、磷酸化等翻译后修饰事件,实现了从“占位驱动”到“事件驱动”的药理学范式跃迁。激酶作为细胞信号网络的核心,其功能异常与多种疾病密切相关,传统激酶抑制剂因依赖ATP口袋结合面临耐药等瓶颈。激酶分子胶作为临近诱导策略的典型应用,通过诱导激酶与E3泛素连接酶或其他调控蛋白的相互作用,实现对激酶功能的降解型或非降解型调控。本文系统综述CRBN类分子胶降解剂(MGDs)、非CRBN类MGDs及非降解型分子胶的研究进展,为激酶分子胶的研发提供参考。

     

    Abstract: The proximity-induced strategy artificially induces spatial proximity between a target protein and an effector protein, triggering post-translational modifications such as ubiquitination and phosphorylation, thereby realizing a pharmacological paradigm shift from "occupancy-driven" to "event-driven" modalities. Within this framework, kinase molecular glues have emerged as a novel class of therapeutic tools that enable the precise regulation of kinase functions by facilitating interactions between kinases and E3 ubiquitin ligases or other regulatory proteins. This review systematically summarizes recent advances in kinase molecular glues, encompassing three major directions: CRBN-based molecular glue degraders (MGDs), non-CRBN MGDs, and non-degrading molecular glues, with the aim of providing a reference for the research and development of molecular glues.

     

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