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.
摘要：
现在已经通过分子胶介导的邻近诱导的降解实现了先前不可药用蛋白质的前所未有的治疗靶向。作为一种小的GTPase，G1至S相变1（GSPT1）与翻译终止因子eRF1相互作用，以促进翻译终止的过程。研究表明，GSPT1在急性髓系白血病（AML）和MYC驱动的肺癌中起着至关重要的作用。因此，针对GSPT1的分子胶（MG）降解剂是治疗AML和MYC驱动的癌症的一种新颖且有前途的方法。从这个角度来看,我们简要总结了GSPT1的结构和功能方面，重点介绍了MG降解剂的最新进展和挑战，以及一些代表性专利。结构-活动关系，强调了MG降解剂的作用机制和药代动力学特征，为GSPT1MG降解剂的合理设计提供了全面的纲要。我们希望提供更新的概述，以及针对GSPT1治疗癌症的策略设计指南。
