Discovery of novel 2,4-diarylaminopyrimidine derivatives as potent and selective epidermal growth factor receptor (EGFR) inhibitors against L858R/T790M resistance mutation

Eur J Med Chem. 2018 May 25:152:298-306. doi: 10.1016/j.ejmech.2018.04.052.

Qi Yan ¹, Yuzhe Chen ², Baiyou Tang ³, Qiang Xiao ¹, Rong Qu ², Linjiang Tong ⁴, Jian Liu ¹, Jian Ding ⁴, Yi Chen ⁴, Ning Ding ¹, Wenfu Tan ⁵, Hua Xie ⁶, Yingxia Li ⁷

Affiliations

1 School of Pharmacy, Fudan University, Shanghai, 201203, China.
2 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
3 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
4 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
5 School of Pharmacy, Fudan University, Shanghai, 201203, China. Electronic address: wftan@fudan.edu.cn.
6 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: hxie@simm.ac.cn.
7 School of Pharmacy, Fudan University, Shanghai, 201203, China. Electronic address: liyx417@fudan.edu.cn.

PMID: 29730192 DOI: 10.1016/j.ejmech.2018.04.052

Abstract

A series of novel 2,4-diarylaminopyrimidine derivatives of AZD9291 were discovered as L858R/T790M mutant selective epidermal growth factor receptor (EGFR) inhibitors. The majority of these compounds exhibited moderate to excellent EGFR T790 M/L858R inhibitory activities and comparable anti-proliferative activities against double mutant over-expressed NCI-H1975 cells to that of AZD9291. The most promising compounds 8a displayed an IC₅₀ of 4.1 nM against EGFR L858R/T790M mutants. 8a also showed excellent cytotoxic effect against NCI-H1975 cells with an IC₅₀ of 59 nM and 100-fold selectivity over wide-type EGFR over-expressed A431 cells. Compound 8a significantly inhibited tumor growth in NCI-H1975 xenograft models at a non-toxic dose. Docking study performed for 8a with ATP binding site of EGFR-TK showed the similar binding mode to that of AZD9291. All these results suggested that compound 8a was a potential mutant-selective EGFR inhibitor.

Keywords

AZD9291; EGFR inhibitors; Mutant selective inhibitors; Pyrimidine derivatives; T790M.

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