生物活性

• 描述The receptor tyrosine kinase, MET proto-oncogene, receptor tyrosine kinase (c-MET) is a high-affinity receptor for hepatocyte growth factor (HGF), and its downstream v-akt murine thymoma viral oncogene homolog (AKT) and mitogen-activated protein kinase (ERK) pathways are regulated by HGF/c-MET. The HGF/c-MET axis is involved in cancer progression, metastasis, and acquired resistance^[3]. HGF/c-MET signaling is often highly activated in tumors because of various mechanisms. MET is a high-affinity tyrosine kinase receptor (RTK) for hepatocyte growth factor (HGF). HGF binding triggers the dimerization of MET receptors, then activation of multiple intracellular pathways such as mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) and focal adhesion kinase (FAK). Tivantinib (ARQ-197) inhibits MET by binding to the inactive conformation of MET to stabilize this conformation. This prevents MET phosphorylation and dampens downstream signaling, thereby resulting in growth inhibition and induction of apoptosis in solid tumors. Tivantinib can induce a G2/M arrest and promoted apoptosis by both intrinsic and extrinsic pathway. Tivantinib is a highly selective, orally administered, non-ATP competitive inhibitor of the MET, with an inhibitory constant (K_i) of 355 nM^[4]. Tivantinib also inhibited constitutive p-MET and HGF-induced p-MET in several type of tumor cells with an IC₅₀ of 100 to 300 nM. In vivo experiment, MHCC97L xenograft mice were treated daily with an oral dose of tivantinib at 100 mg/kg or 200 mg/kg for 15 days. Tivantinib displayed a good anti-tumor effect on MHCC97L xenografts and tumor growth inhibition (TGI) rates were 30.9% and 64.6%, respectively^[4]. In vivo study, EBC-1 cells were treated with the indicated concentrations of Tivantinib and incubated concentrations ranging from 1-10μM for another 72h. It was found that tivantinib treatment inhibited tubulin polymerization in a concentration-dependent manner but did not inhibit c-MET and its downstream AKT and ERK signaling pathways^[3].
• 作用机制Tivantinib(ARQ-197) inhibits MET by binding to the inactive conformation of MET to stabilize this conformation.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  1833/TGL	~100 μM	Growth inhibitory assay	-	GI50=3.7 μM	22027690
  697	10 μM	Growth inhibitory assay	-	EC50=338 nM	19064730
  786-0	10 μM	Growth inhibitory assay	-	IC50=4009 nM	18381444

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• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00557609	Renal Cell Carcinoma (RCC) ... more >> Alveolar Soft Part Sarcoma (ASPS) Clear Cell Sarcoma (CCS) Collapse <<	Phase 2	Completed	-	United States, California ... more >> San Francisco, California, United States, 94143 Santa Monica, California, United States, 90404 United States, Florida Miami, Florida, United States, 33136 United States, Massachusetts Boston, Massachusetts, United States, 02115 United States, Ohio Cincinnati, Ohio, United States, 45229 United States, Texas Dallas, Texas, United States, 75201 Houston, Texas, United States, 77030 Canada, Ontario Toronto, Ontario, Canada, M5G 2M9 United Kingdom London, United Kingdom, SW3 6JJ Collapse <<
  NCT01696955	Head and Neck Squamous Cell Ca... more >>rcinoma Recurrent Head and Neck Carcinoma Collapse <<	Phase 2	Active, not recruiting	-	United States, Arizona ... more >> Mayo Clinic in Arizona Scottsdale, Arizona, United States, 85259 United States, California City of Hope Comprehensive Cancer Center Duarte, California, United States, 91010 USC / Norris Comprehensive Cancer Center Los Angeles, California, United States, 90033 University of California Davis Comprehensive Cancer Center Sacramento, California, United States, 95817 City of Hope South Pasadena South Pasadena, California, United States, 91030 United States, Illinois Northwestern University Chicago, Illinois, United States, 60611 University of Chicago Comprehensive Cancer Center Chicago, Illinois, United States, 60637 Decatur Memorial Hospital Decatur, Illinois, United States, 62526 NorthShore University HealthSystem-Evanston Hospital Evanston, Illinois, United States, 60201 Ingalls Memorial Hospital Harvey, Illinois, United States, 60426 Illinois CancerCare-Peoria Peoria, Illinois, United States, 61615 Southern Illinois University School of Medicine Springfield, Illinois, United States, 62702 United States, Indiana Fort Wayne Medical Oncology and Hematology Inc-Parkview Fort Wayne, Indiana, United States, 46845 Indiana University/Melvin and Bren Simon Cancer Center Indianapolis, Indiana, United States, 46202 United States, Iowa University of Iowa/Holden Comprehensive Cancer Center Iowa City, Iowa, United States, 52242 United States, Maryland University of Maryland/Greenebaum Cancer Center Baltimore, Maryland, United States, 21201 United States, Michigan University of Michigan Comprehensive Cancer Center Ann Arbor, Michigan, United States, 48109 Wayne State University/Karmanos Cancer Institute Detroit, Michigan, United States, 48201 United States, Minnesota Mayo Clinic Rochester, Minnesota, United States, 55905 Metro Minnesota Community Oncology Research Consortium Saint Louis Park, Minnesota, United States, 55416 United States, Missouri Washington University School of Medicine Saint Louis, Missouri, United States, 63110 Mercy Hospital Saint Louis Saint Louis, Missouri, United States, 63141 United States, Pennsylvania Penn State Milton S Hershey Medical Center Hershey, Pennsylvania, United States, 17033-0850 University of Pittsburgh Cancer Institute (UPCI) Pittsburgh, Pennsylvania, United States, 15232 Collapse <<
  NCT01468922	Sarcoma Stoma... more >>ch Neoplasms Neoplasms Collapse <<	Phase 1	Completed	-	United States, Maryland ... more >> National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland, United States, 20892 Collapse <<

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• 参考文献

• [1] Munshi N, Jeay S, et al. ARQ 197, a novel and selective inhibitor of the human c-Met receptor tyrosine kinase with antitumor activity. Mol Cancer Ther. 2010 Jun;9(6):1544-53.

  [2] Comoglio PM, Giordano S, et al. Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov. 2008 Jun;7(6):504-16.

  [3] Aoyama A, Katayama R, Oh-Hara T, Sato S, Okuno Y, Fujita N. Tivantinib (ARQ 197) exhibits antitumor activity by directly interacting with tubulin and overcomes ABC transporter-mediated drug resistance. Mol Cancer Ther. 2014 Dec;13(12):2978-90. doi: 10.1158/1535-7163.MCT-14-0462. Epub 2014 Oct 13. PMID: 25313010.

  [4] Xiang Q, Zhen Z, Deng DY, Wang J, Chen Y, Li J, Zhang Y, Wang F, Chen N, Chen H, Chen Y. Tivantinib induces G2/M arrest and apoptosis by disrupting tubulin polymerization in hepatocellular carcinoma. J Exp Clin Cancer Res. 2015 Oct 12;34:118. doi: 10.1186/s13046-015-0238-2. PMID: 26458953; PMCID: PMC4603939.