How CETSA Generated High Quality Leads For a Challenging Target
University College of London (UCL) was trying to develop small molecule positive modulators of PLCG2 – a challenging membrane associated enzyme target involved in Alzheimers diesease.
For UCL it was critical to prove cellular target engagement to progress their project. They had tried several biophysical/biochemical assays that yielded no significant results. They contacted Pelago Bioscience to see what one of our CETSA-assays could do for their project.
Here’s what we did together:
Initially a CETSA assay was established and primary screening was performed in intact cells. Then the hits were reconfirmed and followed in concentration response.
We could then identify novel chemical matter which was something UCL previously had struggled with.
Then hits were confirmed and validated using CETSA, a biochemical and a cell-based functional assays and this in turn delivered high confidence hits that UCL could use to progress their project.
23 high confidence hits was confirmed and validated.
UCL had these criteria for qualifying the hits:
- CETSA
- Cell based
- Cell free
- No intererence
Insights: Cellular environment with membrane and complexing partners intact – this was key to PLCG2 activation. CETSA screening in intact cells was critical for identification of high quality leads and building confidence in the project.
"While ligand binding assays are commonly used for PK/PD studies in clinical trials of biologics and endogenous protein quantification, Lipum AB sought to establish an orthogonal quantitative LC-MS/MS method for our target protein, bile salt-stimulated lipase (BSSL). We chose Pelago Bioscience as our partner due to their rapid project initiation, collaborative approach, and extensive expertise in processing complex biological samples using high-resolution mass spectrometry. Working with one of the best proteomics labs in the Nordics, Pelago's team delivered high-quality results that aligned perfectly with our clinical research goals."
Ola Sandborgh, CEO
Lipum AB
"At AstraZeneca, we are applying CETSA in hit identification and lead optimization to identify and characterize compounds for a number of novel targets."
Thomas Lundbäck, Senior Director
AstraZeneca
"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
"Using our world leading expertise in CETSA we have created a faster and more efficient drug discovery process. We take great pride in knowing our customers are bringing new medicines to market more quickly thanks to our help."
Michael Dabrowski, CEO and Co-founder
Pelago Bioscience
