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

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.
Fusheng Zhou 1,  Liang Zhang 1,  Yunzhou Jin 1,  Wei Liu 1,  Pengfei Cheng 1,  Xiangyu He 1,  Jing Xie 1,  Sida Shen 1,  Jing Lei 1,  Haixia Ji 1,  Yi Hu 1,  Yingtao Liu 1,  Yumin Cui 1,  Qiang Lv 1,  Jiong Lan 2
Affiliations

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.

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