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

Qi Yan; Yuzhe Chen; Baiyou Tang; Qiang Xiao; Rong Qu; Linjiang Tong; Jian Liu; Jian Ding; Yi Chen; Ning Ding; Wenfu Tan; Hua Xie; Yingxia Li

doi:10.1016/j.ejmech.2018.04.052

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. Epub 2018 Apr 27.

Authors

Qi Yan¹, Yuzhe Chen², Baiyou Tang³, Qiang Xiao¹, Rong Qu², Linjiang Tong⁴, Jian Liu¹, Jian Ding⁴, Yi Chen⁴, Ning Ding¹, Wenfu Tan⁵, Hua Xie⁶, Yingxia Li⁷

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.

MeSH terms

Animals
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / genetics
ErbB Receptors / metabolism
Female
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Models, Molecular
Molecular Structure
Mutation
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / genetics
Neoplasms, Experimental / metabolism
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Pyrimidines
2-aminopyrimidine
EGFR protein, human
ErbB Receptors