Discovery of Potent Azetidine-Benzoxazole MerTK Inhibitors with Target 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 target 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 potently engages the target and demonstrates single agent activity in the immune-driven MC-38 murine syngeneic tumor model.