2RFS

X-ray structure of SU11274 bound to c-Met

Summary for 2RFS

• Entry DOI: 10.2210/pdb2rfs/pdb
• Related: 2RFN
• Descriptor: Hepatocyte growth factor receptor, N-(3-chlorophenyl)-N-methyl-2-oxo-3-[(3,4,5-trimethyl-1H-pyrrol-2-yl)methyl]-2H-indole-5-sulfonamide (3 entities in total)
• Functional Keywords: c-met, receptor tyrosine kinase, su11274, atp-binding, glycoprotein, membrane, nucleotide-binding, phosphorylation, proto-oncogene, transferase, transmembrane, tyrosine-protein kinase
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P08581
• Total number of polymer chains: 1
• Total formula weight: 35802.87

Authors

Bellon, S.F.,Kaplan-Lefko, P.,Yang, Y.,Zhang, Y.,Moriguchi, J.,Dussault, I. (deposition date: 2007-10-01, release date: 2007-11-06, Last modification date: 2023-08-30)

Primary citation

Bellon, S.F.,Kaplan-Lefko, P.,Yang, Y.,Zhang, Y.,Moriguchi, J.,Rex, K.,Johnson, C.W.,Rose, P.E.,Long, A.M.,O'Connor, A.B.,Gu, Y.,Coxon, A.,Kim, T.S.,Tasker, A.,Burgess, T.L.,Dussault, I.
c-Met inhibitors with novel binding mode show activity against several hereditary papillary renal cell carcinoma-related mutations.
J.Biol.Chem., 283:2675-2683, 2008

PubMed Abstract: 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.

PubMed: 18055465
DOI: 10.1074/jbc.M705774200

Experimental method

X-RAY DIFFRACTION (2.2 Å)