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Safety considerations for cereblon-recruiting targeted protein degraders
Helen Garside1, Amy Aslamkhan2, Danette L Daniels3
1ApconiX Ltd. Alderley Park, Macclesfield, UK.
Nature Reviews. Drug Discovery
|April 20, 2026
Summary
Targeted protein degraders (TPDs) recruiting cereblon (CRBN) may degrade unintended proteins, posing safety risks. Developing rigorous methods to assess CRBN-recruiting TPD safety is crucial for drug development.
Area of Science:
- Biochemistry
- Pharmacology
- Drug Development
Background:
- Targeted protein degraders (TPDs) utilizing cereblon (CRBN) show therapeutic promise.
- CRBN-recruiting TPDs can degrade unintended neosubstrates, raising safety concerns.
- Structural similarity to thalidomide links CRBN TPDs to potential teratogenicity.
Purpose of the Study:
- To review CRBN's function and substrate interactions.
- To discuss safety implications of off-target degradation by CRBN TPDs.
- To propose best practices for assessing CRBN-recruiting TPD safety.
Main Methods:
- Literature review of CRBN function, substrates, and TPD mechanisms.
- Analysis of safety liabilities associated with CRBN neosubstrate degradation.
- Discussion of teratogenic potential and organ system toxicities.
Main Results:
- CRBN mediates degradation for molecular glues and proteolysis targeting chimeras.
- Off-target CRBN neosubstrate degradation can lead to toxicity and teratogenicity.
- Current methods for assessing CRBN TPD safety require standardization.
Conclusions:
- Standardized safety assessments are needed for CRBN-recruiting TPDs.
- Monitoring both on-target and off-target degradation is essential.
- Best practices should guide the development of safer CRBN-based therapeutics.
