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

EGFR 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 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 cells. A high-resolution X-ray crystallographic structure was also determined to elucidate the interactions between JND3229 and EGFR. Our study provides an important structural and chemical basis for future development of new generation EGFR inhibitors as anticancer drugs.