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High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
Published on: November 9, 2020
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Targeted Protein Degradation by KLHDC2 Ligands Identified by High Throughput Screening.
Biorxiv : the Preprint Server for Biology
|April 16, 2025
Summary
Researchers identified a new way to target proteins for degradation using Proteolysis targeting chimeras (PROTACs) by finding a novel E3 ligase, KLHDC2. This expands PROTAC technology for potential new therapies.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Drug Discovery
Background:
- Proteolysis targeting chimeras (PROTACs) offer a method for targeted protein degradation.
- Current PROTAC technology is 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 small molecule ligands for previously unexploited E3 ligases.
- To demonstrate the utility of newly identified E3 ligases in PROTAC-mediated protein degradation.
Main Methods:
- High-throughput screening using fluorescence polarization to identify small molecule binders.
- Synthesis of novel PROTACs utilizing the identified E3 ligase binder.
- Cell-based assays to assess protein degradation efficacy.
Main Results:
- A novel small molecule scaffold targeting the ubiquitin E3 ligase KLHDC2 was identified.
- PROTACs incorporating the KLHDC2 ligand demonstrated potent degradation of BRD4 in cellular models.
- This work provides new chemical matter for targeting KLHDC2.
Conclusions:
- The study successfully expanded the range of E3 ligases available for PROTAC development.
- A practical high-throughput screening approach for identifying novel E3 ligase binders was demonstrated.
- This research offers new tools and strategies for targeted protein degradation.
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