Development and therapeutic potential of GSPT1 molecular glue degraders: A medicinal chemistry perspective

IF 10.9 1区医学 Q1 CHEMISTRY, MEDICINAL

Medicinal Research Reviews Pub Date : 2024-02-05 DOI:10.1002/med.22024

Xiujin Chang, Fangui Qu, Chunxiao Li, Jingtian Zhang, Yanqing Zhang, Yuanyuan Xie, Zhongpeng Fan, Jinlei Bian, Jubo Wang, Zhiyu Li, Xi Xu

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引用次数: 0

Abstract

Unprecedented therapeutic targeting of previously undruggable proteins has now been achieved by molecular-glue-mediated proximity-induced degradation. As a small GTPase, G1 to S phase transition 1 (GSPT1) interacts with eRF1, the translation termination factor, to facilitate the process of translation termination. Studied demonstrated that GSPT1 plays a vital role in the acute myeloid leukemia (AML) and MYC-driven lung cancer. Thus, molecular glue (MG) degraders targeting GSPT1 is a novel and promising approach for treating AML and MYC-driven cancers. In this Perspective, we briefly summarize the structural and functional aspects of GSPT1, highlighting the latest advances and challenges in MG degraders, as well as some representative patents. The structure-activity relationships, mechanism of action and pharmacokinetic features of MG degraders are emphasized to provide a comprehensive compendium on the rational design of GSPT1 MG degraders. We hope to provide an updated overview, and design guide for strategies targeting GSPT1 for the treatment of cancer.

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GSPT1 分子胶降解剂的开发和治疗潜力：药物化学的视角。

通过分子胶水介导的近端降解，以前无法药物治疗的蛋白质现在实现了前所未有的靶向治疗。作为一种小 GTPase，G1 到 S 期转换 1（GSPT1）与翻译终止因子 eRF1 相互作用，促进翻译终止过程。研究表明，GSPT1 在急性髓性白血病（AML）和 MYC 驱动的肺癌中发挥着重要作用。因此，靶向 GSPT1 的分子胶（MG）降解剂是治疗 AML 和 MYC 驱动型癌症的一种新颖而有前景的方法。在本视角中，我们简要总结了 GSPT1 的结构和功能，重点介绍了 MG 降解剂的最新进展和挑战，以及一些具有代表性的专利。我们强调了 MG 降解剂的结构-活性关系、作用机制和药代动力学特征，为 GSPT1 MG 降解剂的合理设计提供了一个全面的汇编。希望能为针对 GSPT1 的癌症治疗策略提供最新的概述和设计指南。

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

Medicinal Research Reviews 医学-药学

CiteScore

29.30

自引率

0.00%

发文量

审稿时长

2 months

期刊介绍： Medicinal Research Reviews is dedicated to publishing timely and critical reviews, as well as opinion-based articles, covering a broad spectrum of topics related to medicinal research. These contributions are authored by individuals who have made significant advancements in the field. Encompassing a wide range of subjects, suitable topics include, but are not limited to, the underlying pathophysiology of crucial diseases and disease vectors, therapeutic approaches for diverse medical conditions, properties of molecular targets for therapeutic agents, innovative methodologies facilitating therapy discovery, genomics and proteomics, structure-activity correlations of drug series, development of new imaging and diagnostic tools, drug metabolism, drug delivery, and comprehensive examinations of the chemical, pharmacological, pharmacokinetic, pharmacodynamic, and clinical characteristics of significant drugs.