Case story: CETSA for Target Deconvolution

Application of CETSA for Target Deconvolution

One of the major challenges in phenotypic drug discovery programs is the need for target deconvolution and validation, identifying the specific proteins a drug interacts with. In collaboration with a client, CETSA addressed this issue through unbiased proteome-wide profiling in both intact cells and lysates.

The goal of this proof-of-concept study was to identify the direct targets and elucidate the complete target profile and associated biology of a polyketide lactone with a previously known mechanism of action. The objective was to confirm its direct protein targets and map the full target profile and biological pathways affected, delivering deeper insights to progress the project.

The key questions for the study to answer was:

Can we utilize CETSA for other target deconvolution efforts, comparing intact cell and lysate results, as a strategy to progress other projects and deliver novel therapeutics into the clinic?

The collaboration successfully identified the direct targets and provided valuable insights into its mechanism of action by comparing results from intact cells and lysates. The study supports that it acts as a molecular glue, stabilizing the formation of a complex leading to Golgi disruption, emphasising the importance of studying certain protein-ligand interactions in an intact physiologically relevant cellular environment.

STRATEGIC INSIGHTS: This case study highlights the power of CETSA in phenotypic drug discovery, offering a robust method for target deconvolution and validation without requiring modification of the drug or target. By staying true to the native biological context, CETSA enables more profound understanding and supports the continued advancement of drug discovery programs.

"Pelago Bioscience offers exceptional technical expertise in all aspects of target deconvolution using CETSA – including study design, sample preparation, LC-MS data acquisition, and statistical processing. Our collaboration always proceeded effectively due to Pelago Bioscience's responsiveness, scientific commitment, and dedication to clients resulting in delivery of impactful scientific results."

Benjamin Fontaine, Senior Scientist

LifeMine Therapeutics

“As we approached late preclinical development, our lead compound demonstrated strong efficacy and a favorable toxicity profile.Partnering with Pelago Bioscience, we leveraged their expertise in CETSA technology to successfully identify and validate the protein target. With the comprehensive data package they provided, we met investor requirements and gained the support needed to move forward. The Pelago team´s swift and precise response was invaluable throughout the process, and their scientific excellence made a real difference. We’re highly encouraged by the results and grateful for their outstanding collaboration.”

Martin Bonde, CEO

Inthera Bioscience AG

"Our small molecule drug discovery project was seeking a robust assay allowing to screen against the target of interest expressed in its natural cellular environment. Pelago Bioscience's expertise in drug discovery projects, specifically in the CETSA platform and high throughput screens was the key to achieving our goals. We found Pelago's team to be professional, knowledgeable, flexible and dedicated. We highly recommend Pelago Bioscience for drug discovery projects."

Po-Shun Lee, Chief Medical Officer

Generian

"CETSA data is a keystone in our SAR analysis, and by assessing cellular target engagement of our compounds across multiple cell lines we gain confidence in our project prioritizations."

Peter Joyce, CEO and Co-Founder

Grey Wolf Therapeutics

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