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. 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

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

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

Lingfeng Chen et al. Eur J Med Chem. .

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.

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