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Published on: November 9, 2020
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Targeted protein degradation by KLHDC2 ligands identified by high-throughput screening
Han Zhou1, Tonglian Zhou1, Wenli Yu2
1Department of Chemistry, Scripps Research, La Jolla, United States.
Elife
|June 16, 2025
Summary
Researchers identified a new small molecule targeting the KLHDC2 E3 ligase for proteolysis-targeting chimeras (PROTACs). This expands PROTAC technology, enabling potent degradation of target proteins like BRD4 in cellular models.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Proteolysis-targeting chimeras (PROTACs) offer a method for targeted protein degradation.
- Current PROTAC applications are limited by the small number of routinely used E3 ligases.
Purpose of the Study:
- To identify novel E3 ligases compatible with PROTAC technology.
- To develop new chemical matter for targeting the KLHDC2 E3 ligase.
Main Methods:
- Utilized a fluorescence polarization-based high-throughput screen to identify small molecule binders.
- Synthesized PROTACs utilizing the identified KLHDC2 ligand.
Main Results:
- Discovered a novel small molecule scaffold that targets the ubiquitin E3 ligase KLHDC2.
- Developed PROTACs using the KLHDC2 ligand that effectively degrade BRD4 in cellular assays.
Conclusions:
- The identified KLHDC2 ligand expands the chemical toolbox for PROTAC development.
- This approach provides a viable strategy for discovering new E3 ligase binders for PROTACs.
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