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Profiling CELMoD-Mediated Degradation of Cereblon Neosubstrates
Joel W Thompson1, Thomas Clayton1, Gody Khambatta1
1Bristol Myers Squibb Company, San Diego, CA, USA.
Methods in Molecular Biology (Clifton, N.J.)
|August 25, 2021
Summary
Targeted protein degradation using Cereblon E3 Ligase Modulating Drugs (CELMoDs) offers a new therapeutic approach. Assays are presented to characterize CELMoD-mediated degradation for drug discovery and target validation.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Targeted protein degradation is an emerging therapeutic strategy.
- Cereblon E3 Ligase Modulating Drugs (CELMoDs) leverage this modality by hijacking the Cereblon E3 ligase.
- CELMoDs induce ubiquitination and proteasomal degradation of neosubstrates, targeting previously undruggable proteins.
Purpose of the Study:
- To describe a comprehensive suite of assays for characterizing CELMoD-mediated protein degradation.
- To provide a platform for the discovery and optimization of CELMoDs.
- To support the validation of therapeutic targets degraded by CELMoDs.
Main Methods:
- Cellular substrate degradation assays.
- CELMoD mechanism of action confirmation assays.
- In vitro ubiquitination assays.
- Cereblon binding assays.
Main Results:
- The described assays enable detailed characterization of CELMoD activity.
- Independent assay execution is possible, but combined use offers a robust platform.
- The assays facilitate the study of CELMoD-induced neosubstrate degradation.
Conclusions:
- The presented assay suite is crucial for advancing CELMoD-based therapeutics.
- This platform supports the development of novel drugs targeting undruggable proteins.
- The assays are vital for validating therapeutic targets within the CELMoD modality.
Keywords:
CELMoDCellular neosubstrate degradationCereblonCereblon bindingIn vitro ubiquitinationTargeted protein degradationMore Related Videos
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