c-Met Inhibitors with Novel Binding Mode Show Activity against Several Hereditary Papillary Renal Cell Carcinoma-related Mutations

• Published in: The Journal of biological chemistry 2008-02, Vol.283 (5), p.2675-2683
• Main Authors: Bellon, Steven F., Kaplan-Lefko, Paula, Yang, Yajing, Zhang, Yihong, Moriguchi, Jodi, Rex, Karen, Johnson, Carol W., Rose, Paul E., Long, Alexander M., O'Connor, Anne B., Gu, Yan, Coxon, Angela, Kim, Tae-Seong, Tasker, Andrew, Burgess, Teresa L., Dussault, Isabelle
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M705774200

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.