1. Protein Tyrosine Kinase/RTK
  2. c-Met/HGFR

Tivantinib (Synonyms: ARQ197; ARQ-197; ARQ 197)

Cat. No.: HY-50686 Purity: 99.69%
Data Sheet SDS Handling Instructions

Tivantinib is a novel and highly selective c-Met tyrosine kinase inhibitor with Ki of 355 nM.

For research use only. We do not sell to patients.
Tivantinib Chemical Structure

Tivantinib Chemical Structure

CAS No. : 905854-02-6

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Description

Tivantinib is a novel and highly selective c-Met tyrosine kinase inhibitor with Ki of 355 nM.

IC50 & Target

Ki: 355 nM (c-Met)[1]

In Vitro

Tivantinib (ARQ 197) selectively inhibits c-Met activity in cell-free and cell-based assays. c-Met-expressing cancer cell lines treated with Tivantinib display either a dose-dependent loss of proliferative capacity or caspase-dependent apoptosis that positively correlates with either ligand-dependent c-Met activity or constitutively active c-Met. To examine the biochemical mode of inhibition of Tivantinib, kinetic analyses are done using recombinant human c-Met in a filtermat-based assay. The Km of ATP is 50.5±2.2 μM, which is similar to the Km value of ATP. In these kinetic studies, Tivantinib inhibits human recombinant c-Met with a calculated inhibitory constant (Ki) of ~355 nM. In vitro exposure to Tivantinib inhibits constitutive c-Met phosphorylation in HT29 and MKN-45 cells, and HGF-induced c-Met phosphorylation in MDA-MB-231 and NCI-H441 cells with an IC50 of 100 to 300 nM[1]. Tivantinib is a low-molecular-weight compound, and is the first in class orally available selective inhibitor of c-Met[2].

In Vivo

Pharmacodynamically, the phosphorylation of c-Met in human colon xenograft tumors (HT29) is strongly inhibited by Tivantinib (ARQ 197), as assessed by a dramatic reduction of c-Met autophosphorylation 24 hours after a single oral dose of 200 mg/kg of Tivantinib. This same dosage in mice shows that tumor xenografts are exposed to sustained plasma levels of Tivantinib, consistent with the observed pharmacodynamic inhibition of c-Met phosphorylation and inhibition of proliferation of c-Met harboring cancer cell lines. A Cmax of 5.73 μg/mL (13 μM), an area under the concentration-time curve of 12.1 μg/mL h, and a t1/2 of 2.4 hours are measured. Plasma levels of Tivantinib 10 hours after dosing are determined to be 1.3 μM, >3-fold above the biochemical inhibitory constant of Tivantinib for c-Met[1].

Clinical Trial
NCT Number Sponsor Condition Start Date Phase
NCT00612209 ArQule Cancer, Advanced Solid Tumors April 2007 Phase 1
NCT01152645 Kyowa Hakko Kirin Co., Ltd Gastric Cancer June 2010 Phase 2
NCT01149720 Daiichi Sankyo Inc.|ArQule|ICON Clinical Research Solid Tumors July 2010 Phase 1
NCT01069757 Kyowa Hakko Kirin Co., Ltd Non-small-cell Lung Cancer February 2010 Phase 1
NCT00651638 ArQule Healthy March 2008 Phase 1
NCT01251796 Kyowa Hakko Kirin Co., Ltd Advanced/Recurrent Non-small-cell Lung Cancer December 2010 Phase 1
NCT01395758 ArQule Metastatic Non-Small Cell Lung Cancer July 2011 Phase 2
NCT01075048 Daiichi Sankyo Inc. Metastatic Colorectal Cancer January 2010 Phase 1|Phase 2
NCT00988741 ArQule Unresectable Hepatocellular Carcinoma September 2009 Phase 2
NCT01656265 Kyowa Hakko Kirin Co., Ltd Advanced Hepatocellular Carcinoma July 2012 Phase 1
NCT01178411 ArQule Advanced Solid Tumors August 2010 Phase 1|Phase 2
NCT00802555 ArQule Cirrhosis|Hepatocellular Carcinoma January 2009 Phase 1
NCT00827177 ArQule Advanced Solid Tumors September 2009 Phase 1
NCT00658554 ArQule Healthy April 2008 Phase 1
NCT00874042 ArQule Advanced Solid Tumors March 2009 Phase 1
NCT00302172 ArQule Cancer|Tumor January 2006 Phase 1
NCT00612703 ArQule Cancer February 2008 Phase 1
NCT01055067 Daiichi Sankyo Inc. Non-CNS Germ Cell Tumors (Seminomas and Nonseminomas) January 2010 Phase 2
NCT01580735 Kyowa Hakko Kirin Co., Ltd Non-small-cell Lung Cancer May 2012 Phase 2
NCT00558207 ArQule Pancreatic Neoplasms November 2007 Phase 2
NCT00777309 ArQule Non Small Cell Lung Cancer September 2008 Phase 2
NCT01070290 ArQule Gastric Cancer Phase 2
NCT01377376 Kyowa Hakko Kirin Co., Ltd Non-small-cell Lung Cancer July 2011 Phase 3
NCT00557609 ArQule Renal Cell Carcinoma (RCC)|Alveolar Soft Part Sarcoma (ASPS)|Clear Cell Sarcoma (CCS) October 2007 Phase 2
NCT01468922 National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC) Sarcoma|Stomach Neoplasms|Neoplasms October 24, 2011 Phase 1
NCT00609921 Kyowa Hakko Kirin Co., Ltd Cancer January 2008 Phase 1
NCT01892527 Armando Santoro, MD|Istituto Clinico Humanitas Colorectal Cancer Metastatic|C-met Overexpression March 2013 Phase 2
NCT02608411 Istituto Oncologico Veneto IRCCS Carcinoma, Small Cell October 2015 Phase 2
NCT02029157 Kyowa Hakko Kirin Co., Ltd Liver Cancer January 2014 Phase 3
NCT01699061 Daiichi Sankyo Inc.|Medpace, Inc. Solid Tumors July 2012 Phase 1
NCT02049060 Armando Santoro, MD|Istituto Clinico Humanitas Malignant Pleural Mesothelioma|Nonsquamous Nonsmall Cell Neoplasm of Lung January 2013 Phase 1|Phase 2
NCT01755767 Daiichi Sankyo Inc.|ArQule|Covance Hepatocellular Carcinoma December 2012 Phase 3
NCT01725191 National Cancer Institute (NCI) Childhood Solid Neoplasm October 2012 Phase 1
NCT01749384 National Cancer Institute (NCI) Solid Neoplasm December 6, 2012 Phase 1
NCT01625156 National Cancer Institute (NCI) Adult Solid Neoplasm May 2012 Phase 1
NCT01244191 Daiichi Sankyo Inc.|ArQule Non Squamous, Non-small-cell Lung Cancer November 2010 Phase 3
NCT01447914 National Cancer Institute (NCI) Refractory Multiple Myeloma November 2011 Phase 2
NCT02150733 Daiichi Sankyo Inc.|Medpace, Inc. Hepatic Impairment|Solid Tumor|Cancer April 2014 Phase 1
NCT01861301 National Cancer Institute (NCI) Epithelioid Mesothelioma|Recurrent Malignant Mesothelioma|Sarcomatoid Mesothelioma|Stage II Pleural Mesothelioma|Stage III Pleural Mesothelioma|Stage IV Pleural Mesothelioma January 2013 Phase 2
NCT01575522 National Cancer Institute (NCI) Estrogen Receptor Negative|HER2/Neu Negative|Progesterone Receptor Negative|Recurrent Breast Carcinoma|Stage IV Breast Cancer|Triple-Negative Breast Carcinoma March 2012 Phase 2
NCT01611857 SCRI Development Innovations, LLC|Daiichi Sankyo Inc. Malignant Solid Tumour|Gastroesophageal Cancer July 2012 Phase 1|Phase 2
NCT01696955 National Cancer Institute (NCI) Head and Neck Squamous Cell Carcinoma|Recurrent Head and Neck Carcinoma August 20, 2012 Phase 2
NCT01519414 National Cancer Institute (NCI) Hormone-Resistant Prostate Cancer|Prostate Adenocarcinoma|Recurrent Prostate Carcinoma|Stage IV Prostate Cancer January 2012 Phase 2
NCT01517399 Daiichi Sankyo Inc.|Medpace, Inc. Solid Tumors December 2011 Phase 1
NCT01688973 National Cancer Institute (NCI) Recurrent Renal Cell Carcinoma|Stage III Renal Cell Cancer|Stage IV Renal Cell Cancer|Type 1 Papillary Renal Cell Carcinoma|Type 2 Papillary Renal Cell Carcinoma August 2012 Phase 2
NCT01654965 National Cancer Institute (NCI) Adult Solid Neoplasm July 24, 2012 Phase 1
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References
Preparing Stock Solutions
Concentration Volume (DMSO) Mass 1 mg 5 mg 10 mg
1 mM 2.7069 mL 13.5347 mL 27.0695 mL
5 mM 0.5414 mL 2.7069 mL 5.4139 mL
10 mM 0.2707 mL 1.3535 mL 2.7069 mL
Kinase Assay
[1]

Recombinant c-Met protein (50 ng) comprising residues 974 to 1390 is incubated in a reaction buffer [50 mM Tris-HCl (pH 7.5), 2 mM DTT, 0.1 mM Na3VO4, 10 mM MgCl2, 1 mM EGTA, 0.02 mg/mL bovine serum albumin, and 10% glycerol] with various concentrations of Tivantinib or DMSO in a total volume of 20 μL. After incubating for 20 minutes at room temperature, 20 μL of 20 μM poly-Glu-Tyr substrate and 20 μL of increasing amounts of cold ATP containing 1.5 μCi of [γ-33P]ATP are added to initiate the reaction. The reaction is stopped after 5, 10, 20, 40, and 60 minutes by the addition of 10% phosphoric acid and 10 μL aliquots of the reaction mixture are spotted onto P30 filtermat in triplicate. The filters are washed thrice for 5 minutes with 0.75% phosphoric acid and once with methanol for 2 minutes. The level of radioactivity is determined by using a Wallac TriLux MicroBeta liquid scintillation counter. Nonspecific binding is determined by conducting the assay in the absence of enzyme and then subtracting the value from each of the experimental values. Reaction rates are determined in the linear range of each reaction and GraphPad Prism software is used to calculate the Km and Vmax values[1].

Cell Assay
[1]

Tivantinib (ARQ 197) is prepared in DMSO and stored, and then diluted with appropriate medium before use[1].

HT29, MKN-45, MDA-MB-231, and NCI-H441 (lung cancer) human cancer cells are seeded in 96-well plates overnight in a medium with 10% FBS. Each cell line is optimized for seeding cell number to ensure a similar degree of confluence at the end of the experiment in nontreated (control) wells. The next day, cells are treated with different concentrations of Tivantinib for 24 hours at 37°C. After ARQ 197 treatment, the drug-containing medium is removed, and cells are washed twice with PBS and incubated in a drug-free medium for an additional 48 hours. Cells are then incubated and stained for 4 hours with the MTS reagent (final concentration of 0.5 mg/mL) per well and are lysed. The results are quantitated by spectrophotometry at λ=450 nm[1].

Animal Administration
[1][2]

Tivantinib (ARQ 197) is formulated in polyethylene glycol 400/20% Vitamin E tocopheryl polyethylene glycol succinate (60:40) (Mice)[1].
Tivantinib (ARQ 197) is prepared by dissolving 10 mg in 10 mL methanol (1 mg/mL). The stock solution is further diluted with methanol to obtain working solutions at several concentration levels (Rat)[2].

Mice[1]
Female athymic nude mice are acclimated to the animal housing facility for at least 1 week before the study. Efficacy studies are done in athymic mice bearing HT29, MKN-45, or MDA-MB-231 tumor xenografts to determine the effect of ARQ 197 on tumor growth. Tumor cells [5×106 (HT29) and 8×106 (MKN-45 and MDA-MB-231) cells/animal] are inoculated s.c. on day 0. Tumor dimensions are measured by a digital caliper and tumor volumes are calculated as length×width2/2. When tumors reached a volume of ~100 mm3, mice are randomized into groups and treated daily with orally administered vehicle control or 200 mg/kg Tivantinib formulated in polyethylene glycol 400/20% Vitamin E tocopheryl polyethylene glycol succinate (60:40) at 30 mg/mL, for 5 consecutive days, followed by a 2-day dosing holiday for four cycles. Therefore, each animal received a total of 20 doses. Results are expressed as mean tumor volume±SEM. To assess differences in tumor size between groups, a Mann-Whitney nonparametric t test is performed and significance is defined as P<0.05.
Rat[2]
Six male Sprague-Dawley rats (180-220 g) are used to study the pharmacokinetics of Tivantinib. Diet is prohibited for 12 h before the experiment but water is freely available. Blood samples (0.3 mL) are collected from the tail vein into heparinized 1.5 mL polythene tubes at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 h after oral administration of Tivantinib (10 mg/kg). The samples are immediately centrifuged at 4000g for 8 min. The plasma obtained (100 μL) is stored at -20°C until analysis. Plasma Tivantinib concentration versus time data for each rat is analyzed by DAS (Drug and statistics) software.

References
M.Wt

369.42

Formula

C₂₃H₁₉N₃O₂

CAS No.

905854-02-6

Storage

Please store the product under the recommended conditions in the Certificate of Analysis.

Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

10 mM in DMSO

* "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

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