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: [email protected].
  • 5. Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: [email protected].
  • 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: [email protected].
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 EGFRT790M 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 EGFRT790M-driven NSCLC.

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