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Monitoring Drug Target Engagement in Cells and Tissues Using the Cellular Thermal Shift Assay

2013; American Association for the Advancement of Science; Volume: 341; Issue: 6141 Linguagem: Inglês

10.1126/science.1233606

1095-9203

Daniel Martinez Molina, Rozbeh Jafari, Marina Ignatushchenko, Takahiro Seki, Andreas Larsson, Dan Chen, Lekshmy Sreekumar, Yihai Cao, P. Nordlund,

Advanced Biosensing Techniques and Applications

The efficacy of therapeutics is dependent on a drug binding to its cognate target. Optimization of target engagement by drugs in cells is often challenging, because drug binding cannot be monitored inside cells. We have developed a method for evaluating drug binding to target proteins in cells and tissue samples. This cellular thermal shift assay (CETSA) is based on the biophysical principle of ligand-induced thermal stabilization of target proteins. Using this assay, we validated drug binding for a set of important clinical targets and monitored processes of drug transport and activation, off-target effects and drug resistance in cancer cell lines, as well as drug distribution in tissues. CETSA is likely to become a valuable tool for the validation and optimization of drug target engagement.