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A FRET-Based Assay for the Identification and Characterization of Cereblon Ligands
Iuliia Boichenko1, Silvia Deiss1, Kerstin Bär1
1Department of Protein Evolution, Max Planck Institute for Developmental Biology , Spemannstrasse 35, 72076 Tübingen, Germany.
Abstract:
Cereblon serves as an ubiquitin ligase substrate receptor that can be tuned toward different target proteins by various cereblon-binding agents. This offers one of the most promising avenues for targeted protein degradation in cancer therapy, but cereblon binding can also mediate teratogenic effects. We present an effective assay that is suited for high-throughput screening of compound libraries for off-target cereblon interactions but also can guide lead optimization and rational design of novel cereblon effector molecules.
Insights
Researchers developed a high-throughput assay to screen for off-target cereblon interactions, crucial for advancing targeted protein degradation in cancer therapy while mitigating teratogenic effects.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Cereblon (CRBN) functions as a ubiquitin ligase substrate receptor, enabling targeted protein degradation.
- CRBN-binding agents are promising for cancer therapy but can cause teratogenic effects.
- Understanding and controlling CRBN interactions is vital for therapeutic development.
Purpose of the Study:
- To develop an effective assay for high-throughput screening of compound libraries.
- To identify off-target cereblon interactions.
- To guide lead optimization and rational design of novel cereblon effector molecules.
Main Methods:
- High-throughput screening (HTS) assay development.
- Utilizing cereblon-binding agents.
- Assessing off-target interactions.
Main Results:
- An effective assay for screening compound libraries was established.
- The assay facilitates identification of off-target cereblon interactions.
- The assay supports lead optimization for novel cereblon effectors.
Conclusions:
- The developed assay is valuable for identifying unintended cereblon interactions.
- This tool aids in the rational design of safer and more effective cereblon-based therapeutics.
- The assay supports the advancement of targeted protein degradation strategies in oncology.
