c-Met inhibitors with novel binding mode show activity against several hereditary papillary renal cell carcinoma-related mutations

J Biol Chem. 2008 Feb 1;283(5):2675-83. doi: 10.1074/jbc.M705774200. Epub 2007 Nov 30.


c-Met is a receptor tyrosine kinase often deregulated in human cancers, thus making it an attractive drug target. One mechanism by which c-Met deregulation leads to cancer is through gain-of-function mutations. Therefore, small molecules capable of targeting these mutations could offer therapeutic benefits for affected patients. SU11274 was recently described and reported to inhibit the activity of the wild-type and some mutant forms of c-Met, whereas other mutants are resistant to inhibition. We identified a novel series of c-Met small molecule inhibitors that are active against multiple mutants previously identified in hereditary papillary renal cell carcinoma patients. AM7 is active against wild-type c-Met as well as several mutants, inhibits c-Met-mediated signaling in MKN-45 and U-87 MG cells, and inhibits tumor growth in these two models grown as xenografts. The crystal structures of AM7 and SU11274 bound to unphosphorylated c-Met have been determined. The AM7 structure reveals a novel binding mode compared with other published c-Met inhibitors and SU11274. The molecule binds the kinase linker and then extends into a new hydrophobic binding site. This binding site is created by a significant movement of the C-helix and so represents an inactive conformation of the c-Met kinase. Thus, our results demonstrate that it is possible to identify and design inhibitors that will likely be active against mutants found in different cancers.

MeSH terms

  • Animals
  • Binding Sites
  • Carcinoma, Renal Cell / drug therapy
  • Carcinoma, Renal Cell / enzymology*
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / pathology
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Drug Design
  • Female
  • Humans
  • Indoles / pharmacology
  • Kidney Neoplasms / drug therapy
  • Kidney Neoplasms / enzymology*
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / pathology
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Mutation*
  • Neoplasm Transplantation
  • Piperazines / pharmacology
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / chemistry
  • Proto-Oncogene Proteins c-met / genetics*
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology
  • Quinolines / chemistry
  • Quinolines / pharmacology
  • Recombinant Fusion Proteins / antagonists & inhibitors
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Sulfonamides / pharmacology
  • Transplantation, Heterologous


  • ((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide)
  • 5-(3-fluoro-4-((6-(methyloxy)-7-((3-(4-morpholinyl)propyl)oxy)-4-quinolinyl)oxy)phenyl)-3-methyl-2-(phenylmethyl)-4(3H)pyrimidinone
  • Indoles
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidinones
  • Quinolines
  • Recombinant Fusion Proteins
  • Sulfonamides
  • Proto-Oncogene Proteins c-met

Associated data

  • PDB/2RFN
  • PDB/2RFS