Degrader Development Without Detours: How CETSA® Accelerates Critical Decisions and De-Risks the Path to Clinical Success

When 90% of drug candidates fail in late-stage trials, choosing the right degrader program early can feel like navigating a minefield. CETSA® transforms uncertainty into clarity, delivering data that ensures confident decisions at every step.

Navigating the complexities of targeted protein degraders is akin to exploring uncharted territory in drug discovery. These groundbreaking molecules promise the ability to tackle “undruggable” targets and create therapeutic breakthroughs, but they also come with heightened risks. Inadequate understanding of degrader mechanisms, unintended off-target effects, and missed opportunities to optimize compound efficacy can derail even the most promising projects.

This is where CETSA (Cellular Thermal Shift Assay) emerges as a transformative tool. Developed by Pelago Bioscience, CETSA empowers drug discovery teams with highly relevant data that directly connects preclinical findings to patient outcomes. It does so by measuring the engagement of a degrader with its target, and the downstream effects of degradation, within live cells and under physiological conditions.

Precision Data in a Crowded Space

Drug discovery is not just a science but a high-stakes decision-making process. With multiple degrader programs competing for attention and resources, having a robust, physiologically relevant assessment method is critical. CETSA fills this gap by providing actionable insights into key questions:

Is the degrader reaching its target? CETSA confirms in-cell target engagement for the protein of interest (POI) and the E3 ligase, an essential first step in degrader validation. CETSA offers a complete pharmacological picture of compound activityby correlating target engagement potency with degradation efficiency.
What are the off-target risks? Using CETSA Explore, teams can map the proteomic impact of a degrader across over 5,000 proteins, identifying potential liabilities early. This ensures that selectivity and safety are baked into development strategies.
How can compound efficacy be optimized? High-throughput CETSA Navigate HT provides critical dose-response and degradation data, helping prioritize molecules for lead optimization. Importantly, the method works with unmodified proteins and compounds, eliminating engineering steps that can misrepresent biological behavior.

Accelerating the Path to Decision-Making

A recurring challenge in degrader development is how long it takes to accumulate enough data to decide which programs to advance. CETSA addresses this head-on. Standardized workflows and automated analysis mean that projects progress from sample submission to actionable insights in weeks rather than months.

For example, CETSA’s Selectivity Profiling rapidly evaluates how chemical modifications affect off-target binding. This allows iterative improvements to compound design while providing confidence that lead candidates have favorable selectivity profiles.

Moreover, the translational power of CETSA ensures that what is observed in preclinical assays aligns with what is likely to happen in patients. By working with endogenous proteins and in live cells, CETSA circumvents the uncertainties introduced by engineered systems, offering directly translatable results.

De-Risking for a Competitive Edge

CETSA is not merely a technology; it’s a strategic asset for degrader development. By integrating CETSA early in the drug discovery pipeline, pharmaceutical companies can:

Reduce the risk of late-stage failures by ensuring candidate selection is based on biologically relevant data.
Streamline the path to IND filing with a clear understanding of the mechanism of action and selectivity.
Gain confidence in compound progression, knowing that comprehensive, unbiased insights inform your decisions.

When degrader development demands answers, CETSA provides them, turning the unknown into a competitive advantage.

Curious about how CETSA can mitigate risks and accelerate your degrader programs? Contact us to discuss your ongoing projects and discover how Pelago’s data-driven insights can support your decision-making at every stage.

For additional information, please contact our representative in Japan, Stefan Sandström.