基于不可成药靶点的蛋白降解靶向嵌合体的研究进展

Advances in the study of proteolysis targeting chimeras based on undruggable targets

在与人体疾病相关的致病蛋白中,超80%的蛋白由于缺乏直接调节蛋白功能的活性口袋或口袋较浅而难以被传统小分子抑制剂干预。因此,这些蛋白通常被认为“不可成药”靶点。蛋白降解靶向嵌合体(proteolysis targeting chimera,PROTAC)是一种针对“不可成药”蛋白的突破性药物研发策略,可特异性识别靶蛋白,利用细胞内固有的泛素-蛋白酶体通路降解靶蛋白,以达到治疗疾病的目的。与小分子抑制剂的占位驱动不同,其事件驱动的降解机制不依赖与靶蛋白的高结合率,该机制使得PROTAC在靶向不可成药蛋白方面具有独特优势。本文作者重点综述了PROTAC技术在转录因子、RAS家族、磷酸酶、内在无序蛋白等靶点方面的研究进展,体现PROTAC技术的应用潜力,为后续研发靶向不可成药靶点的PROTAC提供参考。

Over 80%of the pathogenic proteins associated with human disease are difficult to intervene with traditional small molecule inhibitors due to the lack of active pockets or deep pockets that directly regulate protein function.As a result,these proteins are often considered“undruggable targets”.Proteolysis targeting chimeras(PROTAC)is a breakthrough drug development strategy targeting“undruggable”proteins,which can specifically identify target proteins and use inherent ubiquitination in cells to degrade target proteins for the purpose of treating diseases.Unlike the placeholder drive of small molecule inhibitors,its event-driven degradation mechanism does not rely on high binding to target proteins,which gives PROTAC a unique advantage in targeting undruggable proteins.In this paper,we review the progress of PROTAC technology on targets such as transcription factors,the RAS family,phosphatases,intrinsically disordered proteins and other undruggable targets,which demonstrates the application potential of PROTAC technology and provides a reference for the subsequent development of PROTAC targeting undruggable targets.