Discovery of Potent Azetidine-Benzoxazole MerTK Inhibitors with In VivoTarget Engagement

Inhibition of the receptor tyrosine kinase MerTK by small molecules has the potential to augment the immune response to tumors. Potent, selective inhibitors with high levels of in vivotarget engagement are needed to fully evaluate the potential use of MerTK inhibitors as cancer therapeutics. We report the discovery and optimization of a series of pyrazinamide-based type 1.5 MerTK inhibitors bearing an azetidine-benzoxazole substituent. Compound 31potently engages the target in vivoand demonstrates single agent activity in the immune-driven MC-38 murine syngeneic tumor model.