Design, synthesis and evaluation of highly selective pyridone-based class II MET inhibitors

Bioorg Med Chem Lett. 2014 Aug 1;24(15):3351-5. doi: 10.1016/j.bmcl.2014.05.097. Epub 2014 Jun 6.

Abstract

The high incidence of MET oncogene activation in human malignancies has prompted researchers to develop MET inhibitors. As part of our efforts to developing effective and safe therapeutic agents against MET-dependent tumors, a pyridone-based class II MET inhibitor, namely, 1-(4-((2-amino-3-iodopyridin-4-yl)-oxy)-3-fluorophenyl)-N-(4-fluorobenzyl)-4-methoxy-6-oxo-1,6-dihydropyridine-3-carboxamide (3s), was identified. Knowledge of the binding mode of class II MET inhibitors led to the design of new inhibitors that utilize 2-pyridone to conformationally restrain key pharmacophoric groups within the molecule. Integrated molecular docking and SAR studies resulted in the discovery of a novel class of pyridone MET inhibitors with high potency (IC50 of 0.005 μM) and efficient selectivity (>5000 fold) to VEGFR-2, c-Kit and RET kinases.

Keywords: Kinase inhibitor; MET; Pyridone; Selectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / metabolism
  • Pyridones / chemical synthesis
  • Pyridones / chemistry
  • Pyridones / pharmacology*
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Pyridones
  • Proto-Oncogene Proteins c-met