title: ARQ-197, an oral small-molecule inhibitor of c-Met for the treatment of solid tumors.
abstract: ARQ-197 is an oral, selective c-Met inhibitor under development by ArQule Inc, in partnership with Daiichi Sankyo Co Ltd and Asian licensee Kyowa Hakko Kirin Co Ltd, for the potential treatment of solid tumors, including NSCLC, hepatocellular carcinoma and pancreatic cancer, as well as microphthalmia transcription factor-driven tumors. c-Met, a key cell surface receptor tyrosine kinase involved in diverse regulatory functions, is often aberrantly activated in human cancers. While the precise mechanism of action of ARQ-197 remains undefined, data from preclinical studies have demonstrated that ARQ-197 inhibits c-Met activation in numerous human tumor cell lines and specifically targets c-Met in various cancer types; uniquely, ARQ-197 inhibits c-Met in a non-ATP-competitive manner. Phase I/II clinical trials demonstrated promise in terms of both tolerability and tumor response. Intriguingly, dose-limiting adverse effects were hematological in nature. Combinational trials are also ongoing to take advantage of the signaling crosstalk between c-Met and other oncogenic signaling systems. Prioritization of the clinical development of c-Met inhibitors, such as ARQ-197, among different tumor disease types is a key challenge at present; an improved understanding of the prediction of molecular determinants in tumors with respect to c-Met kinase as the driver oncogenic receptor, and of the prediction of tumor response, is still urgently needed.
authors.affiliation: Case Western Reserve University, Ireland Cancer Center, University Hospitals Case Medical Center, Division of Hematology/Oncology, Department of Medicine, 10900 Euclid Avenue, WRB 2-123, Cleveland, OH 44106, USA.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Bagai
authors.forename: Weiwen
authors.initials: W
authors.lastname: Fan
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Ma
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology; D002986:Clinical Trials as Topic; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011760:Pyrrolidinones / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011804:Quinolines / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C551661:ARQ 197; D000970:Antineoplastic Agents; D011760:Pyrrolidinones; D011804:Quinolines; D019859:Proto-Oncogene Proteins c-met