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An engineered cereblon optimized for high-throughput screening and molecular glue discovery
Henry J Bailey1, Jonathan Eisert2, Rubina Kazi3
1Institute of Biochemistry II, Medical Faculty, Goethe-University, Frankfurt am Main and Buchmann Institute for Molecular Life Sciences, Frankfurt am Main, Germany; Max Planck Institute of Biophysics, Max-von-Laue-Strasse 3, 60439 Frankfurt am Main, Germany.
Cell Chemical Biology
|November 29, 2024
Summary
Researchers developed a novel human cereblon (CRBN) construct for efficient production and screening. This tool aids in discovering new molecular glues that target CRBN, advancing the development of targeted protein degraders.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Most clinical degraders use immunomodulatory imide drugs (IMiDs) targeting the cereblon (CRBN) E3 ligase receptor.
- Identifying IMiD molecular glue substrates is challenging and underexplored.
Purpose of the Study:
- To design and validate a human CRBN construct for efficient expression and high-throughput screening.
- To develop methods for identifying novel IMiD molecular glue substrates and determining the IMiD cellular interactome.
Main Methods:
- Engineered homogenous and cost-efficient human CRBN expression in E. coli.
- Developed an "Enamine focused IMiD library" for high-throughput screening.
- Adapted the CRBN construct for proof-of-principle glue screening.
Main Results:
- The CRBN construct demonstrated excellent binding activity and ease of production.
- High-throughput screening identified potent, ligand-efficient, and specific IMiD binders.
- The study enabled IMiD cellular interactome determination through glue screening.
Conclusions:
- The developed CRBN construct and screening methods are valuable tools for discovering next-generation CRBN glues.
- This work facilitates the identification of novel molecular glue substrates for targeted protein degradation.
