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

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 translati...

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Published in:Medicinal research reviews 2024-07, Vol.44 (4), p.1727-1767
Main Authors: Chang, Xiujin, Qu, Fangui, Li, Chunxiao, Zhang, Jingtian, Zhang, Yanqing, Xie, Yuanyuan, Fan, Zhongpeng, Bian, Jinlei, Wang, Jubo, Li, Zhiyu, Xu, Xi
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Cancer therapies
Chemistry, Pharmaceutical
GSPT1
Humans
Leukemia
Lung cancer
molecular glue
Pharmaceutical sciences
Pharmacokinetics
Phase transitions
Proteins
Proteolysis
Structure-Activity Relationship
structure‐activity relationships
targeted protein degradation
translation termination
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Summary: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.
ISSN:0198-6325
1098-1128
1098-1128
DOI:10.1002/med.22024