Design, synthesis and structure-activity relationships of novel biarylamine-based Met kinase inhibitors

Bioorg Med Chem Lett. 2010 May 1;20(9):2998-3002. doi: 10.1016/j.bmcl.2010.01.042. Epub 2010 Jan 20.

Abstract

Biarylamine-based inhibitors of Met kinase have been identified. Lead compounds demonstrate nanomolar potency in Met kinase biochemical assays and significant activity in the Met-driven GTL-16 human gastric carcinoma cell line. X-ray crystallography revealed that these compounds adopt a bioactive conformation, in the kinase domain, consistent with that previously seen with 2-pyridone-based Met kinase inhibitors. Compound 9b demonstrated potent in vivo antitumor activity in the GTL-16 human tumor xenograft model.

MeSH terms

  • Amines / chemistry*
  • Aminopyridines / chemical synthesis*
  • Aminopyridines / chemistry
  • Aminopyridines / pharmacology
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • 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
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays

Substances

  • Amines
  • Aminopyridines
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-met

Associated data

  • PDB/3L8V