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
  • 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: [email protected].
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.