Discovery of selective EGFR modulator to inhibit L858R/T790M double mutants bearing a N-9-Diphenyl-9H-purin-2-amine scaffold

Jinxing Hu; Yufei Han; Jingtao Wang; Yue Liu; Yanfang Zhao; Yajing Liu; Ping Gong

doi:10.1016/j.bmc.2018.02.029

Discovery of selective EGFR modulator to inhibit L858R/T790M double mutants bearing a N-9-Diphenyl-9H-purin-2-amine scaffold

Bioorg Med Chem. 2018 May 1;26(8):1810-1822. doi: 10.1016/j.bmc.2018.02.029. Epub 2018 Feb 17.

Authors

Jinxing Hu¹, Yufei Han¹, Jingtao Wang¹, Yue Liu¹, Yanfang Zhao¹, Yajing Liu², Ping Gong³

Affiliations

¹ Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
² Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China. Electronic address: lyjpharm@126.com.
³ Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China. Electronic address: gongpinggp@126.com.

PMID: 29486953
DOI: 10.1016/j.bmc.2018.02.029

Abstract

Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of N-9-Diphenyl-9H-purin-2-amine derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 23a showed excellent enzyme inhibitory activities and selectivity with nanomolar IC₅₀ values for both the single T790M and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 23a displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R. And it was less potent against A549 (WT EGFR and k-Ras mutation) and HT-29 (non-special gene type) cells, showing a high safety index.

Keywords: L858R/T790M double mutants; N-9-Diphenyl-9H-purin-2-amine derivatives; Non-small cell lung cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Benzene Derivatives / chemical synthesis
Benzene Derivatives / chemistry
Benzene Derivatives / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / genetics
ErbB Receptors / metabolism
HT29 Cells
Humans
Molecular Structure
Mutation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Purines / chemical synthesis
Purines / chemistry
Purines / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Benzene Derivatives
Protein Kinase Inhibitors
Purines
EGFR protein, human
ErbB Receptors