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Updated: Jan 16, 2026
Reporter-based Growth Assay for Systematic Analysis of Protein Degradation
Published on: November 6, 2014
GSPT1 degraders: research progress, development strategies and challenges
Chen Liu1, Hongkang Peng1, Peng Chen1
1School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
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.
Insights
Targeting GSPT1, previously undruggable, is now possible using Cereblon E3 Ligase Modulators (CELMoDs) to degrade the protein. This breakthrough offers a new therapeutic strategy for GSPT1-related cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- GSPT1 dysregulation is implicated in cancer development and progression.
- GSPT1's lack of binding pockets made it an undruggable target.
- Cereblon E3 Ligase Modulators (CELMoDs) offer a novel approach to target GSPT1.
Purpose of the Study:
- To review the progress of GSPT1 degraders.
- To emphasize the design, activity studies, and development strategies of GSPT1 degraders.
- To provide insights for future GSPT1 degrader development.
Main Methods:
- Review of recent studies on CELMoDs and GSPT1 degradation.
- Analysis of GSPT1 degrader design principles.
- Evaluation of activity studies and clinical trial progress.
Main Results:
- CELMoDs induce GSPT1 degradation by recruiting it to Cereblon.
- Several selective GSPT1 degraders have advanced to clinical trials.
- This approach presents a viable therapeutic strategy for GSPT1-related cancers.
Conclusions:
- GSPT1 degraders represent a promising therapeutic avenue for cancer treatment.
- Further development of GSPT1 degraders is warranted.
- CELMoDs have overcome the 'undruggable' nature of GSPT1.
