title: ARQ 197, a novel and selective inhibitor of the human c-Met receptor tyrosine kinase with antitumor activity.
abstract: The met proto-oncogene is functionally linked with tumorigenesis and metastatic progression. Validation of the receptor tyrosine kinase c-Met as a selective anticancer target has awaited the emergence of selective c-Met inhibitors. Herein, we report ARQ 197 as the first non-ATP-competitive small molecule that selectively targets the c-Met receptor tyrosine kinase. Exposure to ARQ 197 resulted in the inhibition of proliferation of c-Met-expressing cancer cell lines as well as the induction of caspase-dependent apoptosis in cell lines with constitutive c-Met activity. These cellular responses to ARQ 197 were phenocopied by RNAi-mediated c-Met depletion and further demonstrated by the growth inhibition of human tumors following oral administration of ARQ 197 in multiple mouse xenograft efficacy studies. Cumulatively, these data suggest that ARQ 197, currently in phase II clinical trials, is a promising agent for targeting cancers in which c-Met-driven signaling is important for their survival and proliferation.
authors.affiliation: Boston Biomedical, Inc., Norwood, Massachusetts, USA.
authors.forename: Neru
authors.initials: N
authors.lastname: Munshi
authors.forename: Sébastien
authors.initials: S
authors.lastname: Jeay
authors.forename: Youzhi
authors.initials: Y
authors.lastname: Li
authors.forename: Chang-Rung
authors.initials: CR
authors.lastname: Chen
authors.forename: Dennis S
authors.initials: DS
authors.lastname: France
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ashwell
authors.forename: Jason
authors.initials: J
authors.lastname: Hill
authors.forename: Magdi M
authors.initials: MM
authors.lastname: Moussa
authors.forename: David S
authors.initials: DS
authors.lastname: Leggett
authors.forename: Chiang J
authors.initials: CJ
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007165:Immunosuppression Therapy; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C551661:ARQ 197; C000715470:MAS1 protein, human; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011758:Pyrroles; D011760:Pyrrolidinones; D011804:Quinolines; D019859:Proto-Oncogene Proteins c-met; D020169:Caspases