Pelago webinar

December 14, 08:00 PST / 17:00 CET

Speakers:

Gizem Akçay

Head of Chemical Biology, Bayer Research and Innovation Center

Tomas Friman

Senior Scientist, Pelago Bioscience

Isabel Martin Caballero

Project Advisor, Pelago Bioscience

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About the webinar

CETSA® Explore is an unbiased mass spectrometry-based, proteome-wide target engagement assessment method for compound profiling measuring not only direct binding but subsequent downstream consequences of the initial target engagement without any label. CETSA® Explore can guide drug discovery projects through target identification, selectivity assessments, and provide insights into biological processes in physiologically relevant conditions.

 

Our speakers will present different application of CETSA® Explore and highlight how this proteome-wide assay can help at various stages of drug discovery.

 

CETSA® enabled deconvolution of cellular targets from a high-throughput phenotypic screen

Gizem Akçay, Head of Chemical Biology, Bayer Research and Innovation Center

 

Using a phenotypic assay to screen thousands of compounds against nearly 500 cell lines, we have identified a molecule with potent and selective activity against cancer cell lines. As part of target deconvolution efforts, CETSA® Explore experiments in intact cells and lysate revealed that compound destabilized a specific target protein. Follow-up, CETSA Navigate studies and rescue experiments with a known inhibitor validated the protein target. Additional studies revealed the role of the target protein in regulating a specific function that results in anti-proliferative activity once perturbed by Bayer compound.

 

CETSA® Explore profiling of histone deacetylase inhibitors

Tomas Friman, Senior Scientist, Pelago Bioscience

 

The Cellular Thermal Shift Assay (CETSA®) is a powerful technique for validating small molecules binding to their cognate protein targets. CETSA® can also be used together with mass spectrometry (MS) detection, which enables target deconvolution of a compound’s on- and off-targets in an unbiased fashion. At Pelago Bioscience we have been running a compound profiling campaign for several years in which determine binding profiles for various drugs and probes. To date, we have profiled over 300 compounds at a single concentration in up to three cell lines. The single concentration of 30 µM has proven sufficiently saturating fort the CETSA® method for most types of compounds. Within this profiling effort we have determined the CETSA® binding profiles of 10 reported histone deacetylase inhibitors (HDACi) belonging to several different inhibitor classes. HDACi are used to inhibit the function of enzymes (HDACs) that regulate the acetylation levels of chromatin, which in turn affects the level of gene transcription. Inhibition of HDACs has been shown to be beneficial when treating malignancies as growth and survival of transformed cells are hampered by HADCi. Several HDACi has entered clinical use for treatment of neoplastic diseases, and a use for HDACi in inflammatory diseases has also been suggested. In the current presentation CETSA® Explore profiles of the HDACi that have been profiled so far and their HDAC binding repertoire as well as some of their common off-targets will be discussed.