Discovery of a 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (MK-2461) inhibitor of c-Met kinase for the treatment of cancer

J Med Chem. 2011 Jun 23;54(12):4092-108. doi: 10.1021/jm200112k. Epub 2011 May 24.

Abstract

c-Met is a transmembrane tyrosine kinase that mediates activation of several signaling pathways implicated in aggressive cancer phenotypes. In recent years, research into this area has highlighted c-Met as an attractive cancer drug target, triggering a number of approaches to disrupt aberrant c-Met signaling. Screening efforts identified a unique class of 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one kinase inhibitors, exemplified by 1. Subsequent SAR studies led to the development of 81 (MK-2461), a potent inhibitor of c-Met that was efficacious in preclinical animal models of tumor suppression. In addition, biochemical studies and X-ray analysis have revealed that this unique class of kinase inhibitors binds preferentially to the activated (phosphorylated) form of the kinase. This report details the development of 81 and provides a description of its unique biochemical properties.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Benzocycloheptenes / chemical synthesis*
  • Benzocycloheptenes / pharmacokinetics
  • Benzocycloheptenes / pharmacology
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Dogs
  • Drug Screening Assays, Antitumor
  • Female
  • Haplorhini
  • Humans
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Mutation
  • Neoplasm Transplantation
  • Phosphorylation
  • Protein Binding
  • Pyrazoles / chemical synthesis
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / pharmacology
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology
  • Rats
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology
  • Transplantation, Heterologous

Substances

  • 5H-benzo(4,5)cyclohepta(1,2-b)pyridin-5-one
  • Antineoplastic Agents
  • Benzocycloheptenes
  • Pyrazoles
  • Pyridines
  • Sulfonamides
  • RON protein
  • Receptor Protein-Tyrosine Kinases