| http://purl.uniprot.org/citations/21454604 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/21454604 | http://www.w3.org/2000/01/rdf-schema#comment | "A number of human malignancies exhibit sustained stimulation, mutation, or gene amplification of the receptor tyrosine kinase human mesenchymal-epithelial transition factor (c-Met). ARQ 197 is a clinically advanced, selective, orally bioavailable, and well tolerated c-Met inhibitor, currently in Phase 3 clinical testing in non-small cell lung cancer patients. Herein, we describe the molecular and structural basis by which ARQ 197 selectively targets c-Met. Through our analysis we reveal a previously undisclosed, novel inhibitory mechanism that utilizes distinct regulatory elements of the c-Met kinase. The structure of ARQ 197 in complex with the c-Met kinase domain shows that the inhibitor binds a conformation that is distinct from published kinase structures. ARQ 197 inhibits c-Met autophosphorylation and is highly selective for the inactive or unphosphorylated form of c-Met. Through our analysis of the interplay between the regulatory and catalytic residues of c-Met, and by comparison between the autoinhibited canonical conformation of c-Met bound by ARQ 197 to previously described kinase domains of type III receptor tyrosine kinases, we believe this to be the basis of a powerful new in silico approach for the design of similar inhibitors for other protein kinases of therapeutic interest."xsd:string |
| http://purl.uniprot.org/citations/21454604 | http://purl.org/dc/terms/identifier | "doi:10.1074/jbc.m110.213801"xsd:string |
| http://purl.uniprot.org/citations/21454604 | http://purl.uniprot.org/core/author | "Eathiraj S."xsd:string |
| http://purl.uniprot.org/citations/21454604 | http://purl.uniprot.org/core/author | "France D.S."xsd:string |
| http://purl.uniprot.org/citations/21454604 | http://purl.uniprot.org/core/author | "Chan T.C."xsd:string |
| http://purl.uniprot.org/citations/21454604 | http://purl.uniprot.org/core/author | "Ashwell M.A."xsd:string |
| http://purl.uniprot.org/citations/21454604 | http://purl.uniprot.org/core/author | "Hirschi M."xsd:string |
| http://purl.uniprot.org/citations/21454604 | http://purl.uniprot.org/core/author | "Palma R."xsd:string |
| http://purl.uniprot.org/citations/21454604 | http://purl.uniprot.org/core/author | "Volckova E."xsd:string |
| http://purl.uniprot.org/citations/21454604 | http://purl.uniprot.org/core/date | "2011"xsd:gYear |
| http://purl.uniprot.org/citations/21454604 | http://purl.uniprot.org/core/name | "J Biol Chem"xsd:string |
| http://purl.uniprot.org/citations/21454604 | http://purl.uniprot.org/core/pages | "20666-20676"xsd:string |
| http://purl.uniprot.org/citations/21454604 | http://purl.uniprot.org/core/title | "Discovery of a novel mode of protein kinase inhibition characterized by the mechanism of inhibition of human mesenchymal-epithelial transition factor (c-Met) protein autophosphorylation by ARQ 197."xsd:string |
| http://purl.uniprot.org/citations/21454604 | http://purl.uniprot.org/core/volume | "286"xsd:string |
| http://purl.uniprot.org/citations/21454604 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/21454604 |
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| http://purl.uniprot.org/uniprot/#_B5A941-mappedCitation-21454604 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/21454604 |