Discovery of JND3229 as a New EGFRC797S Mutant Inhibitor with In Vivo Monodrug Efficacy
3区 · 医学
作者: Lu, Xiaoyun ; Zhang, Tao ; Zhu, Su-Jie ; Xun, Qiuju ; Tong, Lingjiang ; Hu, Xianglong ; Li, Yan ; Chan, Shingpan ; Su, Yi ; Sun, Yiming ; Chen, Yi ; Ding, Jian ; Yun, Cai-Hong ; Xie, Hua ; Ding, Ke
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.