Q3 · MEDICINE
Article
Author: Ding, Ke ; Zhu, Su-Jie ; Tong, Lingjiang ; Hu, Xianglong ; Chan, Shingpan ; Li, Yan ; Xie, Hua ; Sun, Yiming ; Ding, Jian ; Xun, Qiuju ; Su, Yi ; Lu, Xiaoyun ; Zhang, Tao ; Yun, Cai-Hong ; Chen, Yi
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.