Discovery of JND3229 as a New EGFRC797S Mutant Inhibitor with In Vivo Monodrug Efficacy

EGFR C797S mutation inducing resistance against third generation EGFR inhibitor drugs is an emerging “unmet clinical need” for nonsmall cell lung cancer patients. The pyrimidopyrimidinone derivative JND3229 was identified as a new highly potent EGFR C797S inhibitor with single digit nM potency. It also exhibited good in vitro and in vivo monodrug anticancer efficacy in a xenograft mouse model of BaF3/EGFR 19D/T790M/C797S cells. A high-resolution X-ray crystallographic structure was also determined to elucidate the interactions between JND3229 and EGFR T790M/C797S . Our study provides an important structural and chemical basis for future development of new generation EGFR C797S inhibitors as anticancer drugs.