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Eur J Med Chem. 2017 Nov 10;140:510-527. doi: 10.1016/j.ejmech.2017.08.061. Epub 2017 Sep 20.

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

Author information

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.

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

PMID:
28987609
DOI:
10.1016/j.ejmech.2017.08.061
[Indexed for MEDLINE]

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