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

ABSTRACT: EGFRC797S 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 EGFRC797S 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/EGFR19D/T790M/C797S cells. A high-resolution X-ray crystallographic structure was also determined to elucidate the interactions between JND3229 and EGFRT790M/C797S. Our study provides an important structural and chemical basis for future development of new generation EGFRC797S inhibitors as anticancer drugs.

SUBMITTER: Lu X 

PROVIDER: S-EPMC6231186 | biostudies-other | 2018 Nov

REPOSITORIES: biostudies-other

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Discovery of JND3229 as a New EGFR<sup>C797S</sup> Mutant Inhibitor with In Vivo Monodrug Efficacy.

Lu Xiaoyun X   Zhang Tao T   Zhu Su-Jie SJ   Xun Qiuju Q   Tong Lingjiang L   Hu Xianglong X   Li Yan Y   Chan Shingpan S   Su Yi Y   Sun Yiming Y   Chen Yi Y   Ding Jian J   Yun Cai-Hong CH   Xie Hua H   Ding Ke K  

ACS medicinal chemistry letters 20181008 11

EGFR<sup>C797S</sup> 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<sup>C797S</sup> 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<sup>19D/T790M/C797S</sup> cells. A high-resolution X-ray crystallograph  ...[more]