Biologically Relevant Insights for Protein Degraders with CETSA®
Targeted protein degradation has emerged as one of the most exciting innovations in drug discovery. It provides a way to eliminate disease-driving proteins rather than simply inhibiting them. By leveraging the cell’s natural protein degradation systems—such as the ubiquitin-proteasome pathway—small-molecule degraders like molecular glue degraders (MGDs) and proteolysis-targeting chimeras (PROTACs) offer new therapeutic possibilities.
While the potential of degraders is clear, successfully optimizing them for clinical application presents significant challenges. Researchers must answer key questions early in development:
- Is the degrader engaging the intended target inside cells?
- Is the degradation effect specific, or are unintended off-target interactions occurring?
- What are the structure-activity relationships (SAR) that define potency and selectivity?
- Are novel E3 ligases involved in degradation, and how can they be identified?
Traditional biochemical and biophysical assays struggle to provide answers in a physiologically relevant context. Many assays fail to account for cell permeability, protein complex formation, and functional target engagement, leading to misleading data.
Our CETSA (Cellular Thermal Shift Assay) technology addresses these challenges by providing direct, physiologically relevant results of degraders interacting with their targets inside living cells. It enables researchers to measure true target engagement, analyze SAR data, and identify novel protein interactions that might be overlooked.
How CETSA Supports Protein Degrader Development
By integrating CETSA into degrader discovery, researchers can obtain critical insights that traditional methods cannot provide. CETSA allows for:
- Direct confirmation of target engagement in unmodified cellular environments
- Differentiation between functional degraders and silent binders that do not induce degradation
- Unbiased proteome-wide profiling to identify potential off-target effects
- Characterization of degrader-driven interactions with E3 ligases to understand degradation mechanisms
- EC50 and SAR analysis to prioritize the most promising compounds for further development
Using CETSA to Accelerate Drug Discovery
Pharmaceutical and biotech companies are increasingly adopting CETSA for degrader validation and optimization. The assay provides valuable data at multiple stages of discovery, from hit confirmation to lead optimization.
Our latest application note explores real-world applications of CETSA in protein degrader research, including:
- The role of CETSA in confirming degrader-target interactions in living cells
- How CETSA can help identify novel E3 ligases involved in targeted degradation
The impact of CETSA in studying the mechanisms and downstream effects of protein degraders
Want to See CETSA in Action?
Pelago Bioscience specializes in CETSA-powered hit validation and degrader optimization, helping researchers confidently advance their most promising compounds.
Download the complete application note now to discover how CETSA is driving advancements in degrader drug discovery.
