Discovery of N-aryl-N'-pyrimidin-4-yl ureas as irreversible L858R/T790M mutant selective epidermal growth factor receptor inhibitors

Fusheng Zhou; Liang Zhang; Yunzhou Jin; Wei Liu; Pengfei Cheng; Xiangyu He; Jing Xie; Sida Shen; Jing Lei; Haixia Ji; Yi Hu; Yingtao Liu; Yumin Cui; Qiang Lv; Jiong Lan

doi:10.1016/j.bmcl.2017.12.009

Discovery of N-aryl-N'-pyrimidin-4-yl ureas as irreversible L858R/T790M mutant selective epidermal growth factor receptor inhibitors

Bioorg Med Chem Lett. 2018 Apr 15;28(7):1257-1261. doi: 10.1016/j.bmcl.2017.12.009. Epub 2017 Dec 6.

Authors

Fusheng Zhou¹, Liang Zhang¹, Yunzhou Jin¹, Wei Liu¹, Pengfei Cheng¹, Xiangyu He¹, Jing Xie¹, Sida Shen¹, Jing Lei¹, Haixia Ji¹, Yi Hu¹, Yingtao Liu¹, Yumin Cui¹, Qiang Lv¹, Jiong Lan²

Affiliations

¹ Yangtze River Pharmaceutical Group, Shanghai Haiyan Pharmaceutical Technology Co. Itd., No. 8, 67 Libing Road, Shanghai 201203, China.
² Yangtze River Pharmaceutical Group, Shanghai Haiyan Pharmaceutical Technology Co. Itd., No. 8, 67 Libing Road, Shanghai 201203, China. Electronic address: lanjiong@haiyanpharma.com.

PMID: 29534926
DOI: 10.1016/j.bmcl.2017.12.009

Abstract

A novel series of N-aryl-N'-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the EGFR L858R/T790M. The most representative compound 28 showed high activity against EGFR L858R/T790M kinase (IC₅₀ = 4 nM) and 22-fold selectivity against wild type EGFR. Moreover, compound 28 potently inhibited EGFR L858R/T790M phosphorylation (IC₅₀ = 41 nM) and cellular proliferation (IC₅₀ = 37 nM) in the H1975 cell line, while being significantly less toxic to A431 cells. Further, compound 28 exhibited a great selectivity in a mini-panel of kinases.

Keywords: EGFR T790M; Inhibitors; Non-small cell lung cancer; Pyrimidine-4-yl urea.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / 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
Humans
Molecular Docking Simulation
Molecular Structure
Mutation
Phosphorylation / drug effects
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Urea / analogs & derivatives
Urea / chemistry
Urea / pharmacology*

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Urea
EGFR protein, human
ErbB Receptors