Reliable data probing the disease-related hypothesis for a potential therapeutic target is crucial throughout the drug discovery and development process. The ultimate target validation is not achieved until the proof-of-concept study in phase 2 patient trials. However, early indication of the correlation between efficacy and target engagement decreases the risk for late–stage failures and strengthens the protein target validation earlier in preclinical stages.
Therefore, one of the greatest strengths of CETSA® is the ability to confirm that the compound–mediated cellular effects are a consequence of binding to the target in cells or tissue. A good correlation between the desired functional readout and cellular or tissue target engagement to a target protein is a strong indication of its involvement in the biological pathway and strengthens the target validation.
Shaw J, Dale I, Hemsley P, Leach L, et al. Positioning High-Throughput CETSA in Early Drug Discovery through Screening against B-Raf and PARP1. (2019) SLAS Discov. DOI: 10.1177/2472555218813332
Tsuyoshi Ishii, Takuro Okai, Misa Iwatani-Yoshihara, et al. CETSA quantitatively verifies in vivo target engagement of novel RIPK1 inhibitors in various biospecimens. (2017) Nature Scientific Reports. DOI: 10.1038/s41598-017-12513-1