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

Xiaoyun Lu; Tao Zhang; Su-Jie Zhu; Qiuju Xun; Lingjiang Tong; Xianglong Hu; Yan Li; Shingpan Chan; Yi Su; Yiming Sun; Yi Chen; Jian Ding; Cai-Hong Yun; Hua Xie; Ke Ding

doi:10.1021/acsmedchemlett.8b00373

Discovery of JND3229 as a New EGFR^C797S Mutant Inhibitor with In Vivo Monodrug Efficacy

ACS Med Chem Lett. 2018 Oct 8;9(11):1123-1127. doi: 10.1021/acsmedchemlett.8b00373. eCollection 2018 Nov 8.

Authors

Xiaoyun Lu¹, Tao Zhang^{2

3

4}, Su-Jie Zhu⁵, Qiuju Xun⁶, Lingjiang Tong², Xianglong Hu¹, Yan Li², Shingpan Chan¹, Yi Su², Yiming Sun², Yi Chen², Jian Ding², Cai-Hong Yun⁵, Hua Xie², Ke Ding¹

Affiliations

¹ International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
² Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
³ School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China.
⁴ School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
⁵ Department of Biophysics and Peking University Institute of Systems Biomedicine, Peking University Health Science Center, Beijing 100191, China.
⁶ Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, China.

Abstract

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.