Synthesis and evaluation of a series of pyridine and pyrimidine derivatives as type II c-Met inhibitors

Bioorg Med Chem. 2017 Jun 15;25(12):3195-3205. doi: 10.1016/j.bmc.2017.04.003. Epub 2017 Apr 5.

Abstract

In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC50=127nM against EBC-1 cell line) as well as an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that 13d inhibited c-Met phosphorylation in EBC-1 cells in a dose-dependent manner, with complete abolishment at 0.1mM. All these experimental results suggested that 13d could be served as a promising lead compound for the development of anticancer agents.

Keywords: Anti-cancer; Inhibitor; Pyridine; Pyrimidine; Type II; c-Met.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Docking Simulation
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / metabolism
  • Pyridines / chemistry*
  • Pyridines / pharmacology*
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology*

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyrimidines
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • pyrimidine