GSPT1 degraders: research progress, development strategies and challenges

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2025-09-13 DOI:10.1016/j.bmc.2025.118390

Chen Liu , Hongkang Peng , Peng Chen , Yuxiang Li , Zihao Deng , Shaojie Li , Tong Yang , Ke Liu , Zhen Wang , Linyi Liu

引用次数: 0

Abstract

Dysregulation of GSPT1 which is a critical translation termination factor plays an important role in oncogenesis and cancer progression. However, GSPT1 lacks suitable binding pockets and has long been considered an “undruggable” target. Recent studies have revealed that Cereblon E3 Ligase Modulators (CELMoDs), a class of molecular glue-type protein degraders, can bind to the E3 ubiquitin ligase substrate receptor Cereblon and induce Cereblon to recruit GSPT1, leading to GSPT1 degradation. This breakthrough provides a novel therapeutic strategy for GSPT1-related cancers. Currently, several selective GSPT1-degraders have entered clinical trials. This review summarized the research progress of various GSPT1 degraders with an emphasis on their design, activity studies and development strategy, aiming to provide valuable insights for the further development of GSPT1 degraders.

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GSPT1降解剂：研究进展、发展策略与挑战

GSPT1是一个关键的翻译终止因子，其失调在肿瘤发生和癌症进展中起着重要作用。然而，GSPT1缺乏合适的绑定袋，长期以来被认为是“不可药物”的目标。最近的研究发现，Cereblon E3 Ligase Modulators （CELMoDs）是一类分子胶型蛋白降解物，可以结合E3泛素连接酶底物受体Cereblon，诱导Cereblon募集GSPT1，导致GSPT1降解。这一突破为gspt1相关癌症提供了一种新的治疗策略。目前，几种选择性gspt1降解剂已进入临床试验阶段。本文综述了各种GSPT1降解剂的研究进展，重点介绍了GSPT1降解剂的设计、活性研究和开发策略，旨在为GSPT1降解剂的进一步开发提供有价值的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.