biostudies-literatureLu XGovernment of Guangdong ProvinceGuangzhou City Key Laboratory of Precision Chemical Drug Development, Jinan UniversityJinan UniversityNatural Science Foundation of Guangdong ProvinceNational Natural Science Foundation of ChinaInstitutes for Drug Discovery and Development, Chinese Academy of Science1123-1127https://www.ebi.ac.uk/biostudies/studies/S-EPMC6231186biostudies-literatureUnknown9(11)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.ACS medicinal chemistry lettersDiscovery of JND3229 as a New EGFR^C797S Mutant Inhibitor with In Vivo Monodrug Efficacy.PMC6231186312707692015A03030604281673285215722302170207581425021CASIMM01201850062018050100072105A030312014Lu XTong LHu XXun QDing JSun YDing KYun CHLi YZhang TZhu SJXie HChen YSu YChan SfalseDiscovery of JND3229 as a New EGFR^C797S 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.2018-01-01T00:00:00Z2018 Nov2026-05-06T03:42:52.543Z2019-11-15T08:03:51ZS-EPMC62311863042995610.1021/acsmedchemlett.8b00373