CETSA® in Whole Blood: Cutting Waste, Reducing Risk, and Improving Decision Quality in Drug Discovery
The pressure to validate early decisions has never been greater for pharmaceutical R&D teams navigating rising costs and stubbornly high attrition rates. CETSA® (Cellular Thermal Shift Assay), especially in its whole blood application, offers a rare combination of scientific precision and operational impact.
CETSA measures target engagement—the actual binding of a drug to its intended protein target—directly in physiologically relevant conditions. When applied to whole blood, it allows this measurement in unmodified, intact blood cells. There is no need for protein tagging, engineered systems, or chemical probes. This results in data that reflects real biological behaviour, not laboratory artefacts.
The Problem It Solves
Much of today’s early drug discovery still relies on artificial systems: overexpressed proteins in cell lines, tagged compounds, purified proteins in buffer. These simplify assays but distort reality. The consequence is well known—nearly half of clinical trial failures are due to lack of efficacy, often because compounds do not engage their target in vivo.
Whole blood CETSA solves this by confirming drug-target binding under conditions much closer to the clinical setting. It delivers early evidence of biological relevance, making it easier to decide whether to progress or stop a compound before significant time and money are committed.
Where It Fits in the Pipeline
CETSA Whole Blood is typically used in these scenarios:
- Early-stage validation: Confirming that a compound binds to its target before entering lead optimization.
- Tool compound evaluation: Establishing whether a chemical probe or drug scaffold works in a native environment.
- Translational bridging: Using the same assay principle across preclinical and clinical samples to support consistent decision-making.
- Mechanism of action studies: Disentangling primary effects from downstream or off-target responses.
- Support for new modalities: Assessing dual-target engagement in protein degraders (e.g., POI and E3 ligase).
Business Value: Faster Answers, Lower Risk
Pelago’s CETSA workflow in whole blood delivers usable data in as little as four weeks. This speed allows teams to prioritize leads, de-select weak candidates, and allocate resources with more confidence.
The economic impact is significant. One late-stage clinical failure can cost over $800 million. A false positive in early screening that escapes into development is not just a scientific misstep—it’s a financial liability. CETSA reduces this risk by providing early, high-confidence data.
Moreover, its matrix-agnostic design allows the same assay to be used from in vitro to in vivo to ex vivo human samples. This eliminates the risk of changing technologies midstream and introducing new variability.
Limitations and Considerations
CETSA is not without caveats. It can produce false negatives if a drug binds its target without stabilizing it thermally—a condition CETSA depends on. In whole blood, throughput is moderate; advanced setups like proteome-wide CETSA-MS offer more coverage but come at higher cost and require significant mass spectrometry capacity.
It also does not offer detailed binding kinetics or thermodynamic profiling. For that, techniques like SPR or ITC remain essential.
In addition, although the method has been validated across several targets and compound types, it is less established in areas requiring real-time tracking or kinetic measurement in live systems.
Conclusion
CETSA in whole blood is not a panacea, but it is a strong choice when clarity, relevance, and decision speed matter. It reduces the risk of false positives, trims wasted investment, and supports smoother regulatory and clinical transitions.
For R&D leaders balancing risk, time, and cost, this is a tool that earns its place early in the process—when the cost of a mistake is still low, and the potential for course correction is high.
If you are interested, please feel warmly welcome to reach out to our Japan representative, Stefan Sandstrom. We sincerely look forward to the opportunity to support your drug discovery projects.
