Structure-based design and synthesis of 2,4-diaminopyrimidines as EGFR L858R/T790M selective inhibitors for NSCLC

Eur J Med Chem. 2017 Nov 10:140:510-527. doi: 10.1016/j.ejmech.2017.08.061.

Lingfeng Chen ¹, Weitao Fu ², Chen Feng ², Rong Qu ³, Linjiang Tong ³, Lulu Zheng ², Bo Fang ², Yinda Qiu ², Jie Hu ², Yuepiao Cai ², Jianpeng Feng ², Hua Xie ³, Jian Ding ⁴, Zhiguo Liu ⁵, Guang Liang ⁶

Affiliations

1 School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu, 210094, China; Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
2 Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
3 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
4 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: jding@simm.ac.cn.
5 Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: lzgcnu@163.com.
6 School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu, 210094, China; Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: wzmcliangguang@163.com.

PMID: 28987609 DOI: 10.1016/j.ejmech.2017.08.061

Abstract

Mutated epidermal growth factor receptor (EGFR) is a major driver of non-small cell lung Cancer (NSCLC). The EGFR^T790M secondary mutation has become a leading cause of clinically-acquired resistance to gefitinib and erlotinib. Herein, we present a structure-based design approach to increase the potency and selectivity of the previously reported reversible EGFR inhibitor 7, at the kinase and cellular levels. Three-step structure-activity relationship exploration led to promising compounds 19e and 19h with unique chemical structure and binding mode from the Other third-generation tyrosine kinase inhibitors. In a human NSCLC xenograft model, 19e and 19h exhibited dose-dependent tumor growth suppression without toxicity. These selective inhibitors are promising drug candidates for EGFR^T790M-driven NSCLC.

Keywords

Epidermal growth factor receptor; Mutant-selective; Non-small cell lung cancer; T790M; Tyrosine kinase inhibitors.

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