Tivantinib (ARQ 197)

Tivantinib (ARQ 197) is the first non-ATP-competitive c-Met inhibitor with Ki of 0.355 μM, little activity to Ron, and no inhibition to EGFR, InsR, PDGFRα or FGFR1/4. Phase 3.

Price Stock Quantity  
USD 110 In stock
USD 470 In stock
Bulk Inquiry

Massive Discount Available

Free Overnight Delivery on all orders over $ 500.

Tivantinib (ARQ 197) Chemical Structure

Tivantinib (ARQ 197) Chemical Structure
Molecular Weight: 369.42

Validation & Quality Control

Customer Reviews(1)

Quality Control & MSDS

Related Compound Libraries

Tivantinib (ARQ 197) is available in the following compound libraries:

c-Met Inhibitors with Unique Features

  • Non-specific c-Met Inhibitor

    BMS-777607 C-Met, IC50=3.9 nM;Axl, IC50=1.1 nM; Ron, IC50=1.8 nM; Tyro3, IC50=4.3 nM.

  • Most Potent c-Met Inhibitor

    INCB28060 C-Met, IC50=0.13 nM.

  • FDA-approved Inhibitor

    Crizotinib (PF-02341066) Approved by FDA for non-small cell lung carcinoma (NSCLC).

  • Newest c-Met Inhibitor

    EMD 1214063 Potent and selective c-Met inhibitor with IC50 of 4 nM, >200-fold selective for c-Met than IRAK4, TrkA, Axl, IRAK1, and Mer.

Product Information

  • Compare c-Met Inhibitors
    Compare c-Met Products
  • Research Area

Product Description

Biological Activity

Description Tivantinib (ARQ 197) is the first non-ATP-competitive c-Met inhibitor with Ki of 0.355 μM, little activity to Ron, and no inhibition to EGFR, InsR, PDGFRα or FGFR1/4. Phase 3.
Targets c-Met [1]
IC50 0.355 μM(Ki)
In vitro ARQ-197 has been shown to prevent HGF/c-met induced cellular responses in vitro. ARQ-197 possesses antitumor activity; inhibiting proliferation of A549, DBTRG and NCI-H441 cells with IC50 of 0.38, 0.45, 0.29 μM. Treatment with ARQ-197 results in a decrease in phosphorylation of the MAPK signaling cascade and prevention of invasion and migration. In addition, ectopic expression of c-Met in NCI-H661, a cell line having no endogenous expression of c-Met, causes it to acquire an invasive phenotype that is also suppressed by ARQ-197. Although the addition of increasing concentrations of ARQ-197 does not significantly affect the Km of ATP, exposure of c-Met to 0.5 μM ARQ-197 decreased the Vmax of c-Met by approximately 3-fold. The ability of ARQ-197 to decrease the Vmax without affecting the Km of ATP confirmed that ARQ-197 inhibits c-Met through a non–ATP-competitive mechanism and may therefore account for its high degree of kinase selectivity. ARQ-197 prevents human recombinant c-Met with a calculated inhibitory constant Ki of approximately 355 nM. Although the highest concentration of ATP used is 200 μM, the potency of ARQ-197 against c-Met is not reduced by using concentrations of ATP up to 1 mM. ARQ-197 blocks c-Met phosphorylation and downstream c-Met signaling pathways. ARQ-197 suppresses constitutive and ligand-mediated c-Met autophosphorylation and, by extension, c-Met activity, in turn leading to the inhibition of downstream c-Met effectors. ARQ-197 induction of caspase-dependent apoptosis is increased in c-Met–expressing human cancer cells including HT29, MKN-45, and MDA-MB-231 cells.[1][2]
In vivo All three xenograft models treated with ARQ-197 display reductions in tumor growth: 66% in the HT29 model, 45% in the MKN-45 model, and 79% in the MDA-MB-231 model. In these xenograft studies, no significant body weight changes following oral administration of ARQ-197 at 200 mg/kg are observed. Pharmacodynamically, the phosphorylation of c-Met in human colon xenograft tumors (HT29) is strongly inhibited by ARQ-197, as assessed by a dramatic reduction of c-Met autophosphorylation 24 hours after a single oral dose of 200 mg/kg of ARQ-197. This same dosage in mice exhibits that tumor xenografts are exposed to sustained plasma levels of ARQ-197, consistent with the observed pharmacodynamic inhibition of c-Met phosphorylation and inhibition of proliferation of c-Met harboring cancer cell lines. Plasma levels of ARQ-197 10 hours after dosing are determined to be 1.3 μM, more than 3-fold above the biochemical inhibitory constant of ARQ-197 for c-Met. Therefore, ARQ-197 is able to suppress its target in vivo in the xenografted human tumor tissue. In conclusion, ARQ-197 inhibits the growth of c-Met-dependent xenografted human tumors.[1]
Features The first selective c-Met inhibitor to be advanced into human clinical trials.

Protocol(Only for Reference)

Kinase Assay: [1]

c-Met SDS-PAGE in vitro kinase assay Recombinant c-Met protein (100 ng) is preincubated with increasing concentrations of ARQ-197 for 30 minutes at room temperature. Following preincubation, 100 μM of poly-Glu-Tyr substrate and various concentrations of ATP containing 5 μCi of [γ-32P]ATP are added to the reaction mixture. The reaction is incubated for 5 minutes at room temperature and then stopped by the addition of 5 μL of SDS-polyacrylamide gel, reducing sample buffer. The samples are then loaded onto a 7.5% acrylamide gel and SDS-PAGE is performed. The phosphorylated poly-Glu-Tyr substrates are ultimately visualized by autoradiography. c-Met activity is quantified by densitometry.

Cell Assay: [1]

Cell lines T29, MKN-45 and MDA-MB-231 cells
Concentrations 0.03-10 μM
Incubation Time 24, 32, and 48 hours
Method HT29, MKN-45, and MDA-MB-231 cells are seeded in black 96-well plates at 5 × 103 cells per well overnight in a medium with 10% FBS. The next day, cells are treated with increasing concentrations of ARQ-197 (0.03-10 μM) for 24, 32, and 48 hours at 37 °C. After ARQ-197 treatment, the drug-containing medium is removed and cells are incubated for at least 10 minutes in a labeling solution (10 mM HEPES, 140 mM NaCl, and 6 mM CaCl2) containing 2 μg/mL Hoescht 33342 (blue channel), 500-times diluted Annexin V-FITC (green channel), and 1 μg/mL propidium iodide (red channel). High-content image acquisition and analysis are carried out. The program is set to take four images per well. The exposure time is set at 16.7 ms/10% gain, 500 ms/35% gain, and 300 ms/30% gain for the 4,6-diamidino-2-phenylindole, FITC, and rhodamine channels, respectively. Images are processed and the numbers of positive cells for each channel and each condition are determined. In addition, HT29 cells are treated with increasing concentrations of ARQ-197 for 32 hours in the absence or the presence of 25, 50, and 100 μM ZvAD-FMK (irreversible general caspase inhibitor), and the same procedures are undertaken. All experiments are done in triplicate. To determine whether the apoptotic effect is due to c-Met inhibition, the effect of ARQ-197 when glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and c-Met are knocked down using siRNA is investigated. HT29, MKN-45, and MDA-MB-231 cells are transfected with a nontargeted control siRNA, a gapgh-targeted control siRNA, or a met-targeted siRNA. After 3 days, c-Met, GAPDH, and β-actin expression levels are determined using specific antibodies. To determine if the effect is caspase dependent, HT29, MKN-45, and MDA-MB-231 cells are transfected with a met-targeted siRNA for 2 days and incubated in the absence or the presence of increasing concentrations of ZvAD-FMK for 1 additional day. A nontargeted siRNA and a gapgh-targeted siRNA (siRNA GAPDH) are also transfected in parallel, as controls. Cells are then stained with Annexin V-FITC and propidium iodide, and the percentage of apoptotic cells is determined.

Animal Study: [1]

Animal Models Female athymic nude mice bearing HT29, MKN-45, or MDA-MB-231 tumor xenografts
Formulation In polyethylene glycol 400/20% Vitamin E tocopheryl polyethylene glycol succinate (60:40) 30 mg/mL
Dosages 200 mg/kg
Administration Orally administered
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, , 30 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Munshi N, et al. Mol Cancer Ther. 2010, 9(6), 1544-1553.

[2] Comoglio PM, et al. Nat Rev Drug Discov, 2008, 7(6), 504-516.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-09-01)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02150733 Recruiting Hepatic Impairment|Solid Tumor|Cancer Daiichi Sankyo Inc.|Medpace, Inc. April 2014 Phase 1
NCT02029157 Recruiting Liver Cancer Kyowa Hakko Kirin Company, Limited January 2014 Phase 3
NCT01892527 Recruiting Colorectal Cancer Metastatic|C-met Overexpression Istituto Clinico Humanitas|Armando Santoro, MD March 2013 Phase 2
NCT02049060 Recruiting Malignant Pleural Mesothelioma|Nonsquamous Nonsmall Cell Neoplasm of Lung Istituto Clinico Humanitas|Armando Santoro, MD January 2013 Phase 1|Phase 2
NCT01861301 Active, not recruiting Epithelial Mesothelioma|Recurrent Malignant Mesothelioma|Sarcomatous Mesothelioma|Stage II Malignant Mesothelioma|Stage III Malignant Mesothelioma|  ...more Epithelial Mesothelioma|Recurrent Malignant Mesothelioma|Sarcomatous Mesothelioma|Stage II Malignant Mesothelioma|Stage III Malignant Mesothelioma|Stage IV Malignant Mesothelioma National Cancer Institute (NCI) January 2013 Phase 2

view more

Chemical Information

Download Tivantinib (ARQ 197) SDF
Molecular Weight (MW) 369.42
Formula

C23H19N3O2

CAS No. 905854-02-6
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 74 mg/mL (200 mM)
Water <1 mg/mL (<1 mM)
Ethanol 12 mg/mL (32 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol, 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name (3R,4R)-3-(2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-6-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione

Research Area

Customer Reviews (1)


Click to enlarge
Rating
Source Cell Signal. 2013 Sep 4;25(12):2652-2660. Tivantinib (ARQ 197) purchased from Selleck
Method luciferase assays
Cell Lines MDA-MB-231 cells
Concentrations 0.01-10 ng/mL
Incubation Time 24 h
Results HGF increased the transcriptional activity of 210 ETS-1 in a dose-dependent manner (A). The EC50 was 1.041 ±0.24 ng/mL, and the R 2 and p values were 0.97 and 0.0065, respectively. C-Met inhibitor ARQ-197 almost blocked ETS-1 activity induced by HGF at a concentration of 3 μmol/L. The IC50 was 0.21 ± 0.04 μmol/L, and the R 2 and p values were 0.96 and 0.0075, respectively (B).

Product Citations (1)

Tech Support & FAQs

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Tel: +1-832-582-8158 Ext:3

If you have any other enquiries, please leave a message.

* Indicates a Required Field

Related c-Met Products

  • EMD 1214063

    EMD 1214063 is a potent and selective c-Met inhibitor with IC50 of 4 nM, >200-fold selective for c-Met than IRAK4, TrkA, Axl, IRAK1, and Mer. Phase 1.

  • CO-1686 (AVL-301)

    CO-1686 is an irreversible, mutant-selective EGFR inhibitor with Ki of 21.5 nM and 303.3 nM for EGFRL858R/T790M and EGFRWT, respectively. Phase 2.

  • AZD9291

    AZD9291 is an oral, irreversible, and mutant-selective EGFR inhibitor with IC50 of 12.92, 11.44 and 493.8 nM for Exon 19 deletion EGFR, L858R/T790M EGFR, and WT EGFR, respectively. Phase 3.

  • Crizotinib (PF-02341066)

    Crizotinib (PF-02341066) is a potent inhibitor of c-Met and ALK with IC50 of 11 nM and 24 nM, respectivley.

  • PHA-665752

    PHA-665752 is a potent, selective and ATP-competitive c-Met inhibitor with IC50 of 9 nM, >50-fold selectivity for c-Met than RTKs or STKs.

  • Foretinib (GSK1363089)

    Foretinib (GSK1363089) is an ATP-competitive inhibitor of HGFR and VEGFR, mostly for Met and KDR with IC50 of 0.4 nM and 0.9 nM. Less potent against Ron, Flt-1/3/4, Kit, PDGFRα/β and Tie-2, and little activity to FGFR1 and EGFR. Phase 2.

  • SU11274

    SU11274 is a selective Met inhibitor with IC50 of 10 nM, no effects on PGDFRβ, EGFR or Tie2.

  • BMS-777607

    BMS-777607 is a Met-related inhibitor for c-Met, Axl, Ron and Tyro3 with IC50 of 3.9 nM, 1.1 nM, 1.8 nM and 4.3 nM, 40-fold more selective for Met-related targets versus Lck, VEGFR-2, and TrkA/B, and more than 500-fold greater selectivity versus all other receptor and non receptor kinases. Phase 1/2.

    Features:A potent inhibitor of the Met family, and >40-fold selectivity vs. Lck, VEGFR2, and TrkA/B and >500-fold selective vs. other receptor and non-receptor kinases.

  • PF-04217903

    PF-04217903 is a selective ATP-competitive c-Met inhibitor with IC50 of 4.8 nM, susceptible to oncogenic mutations (no activity to Y1230C mutant). Phase 1.

  • INCB28060

    INCB28060 is a novel, ATP-competitive inhibitor of c-MET with IC50 of 0.13 nM, inactive against RONβ, as well as EGFR and HER-3. Phase 1.

    Features:Inactive against RONβ, another member of the c-MET RTK family, as well as EGFR and HER-3 (members of the EGFR RTK family).

Recently Viewed Items

Tags: buy Tivantinib (ARQ 197) | Tivantinib (ARQ 197) supplier | purchase Tivantinib (ARQ 197) | Tivantinib (ARQ 197) cost | Tivantinib (ARQ 197) manufacturer | order Tivantinib (ARQ 197) | Tivantinib (ARQ 197) distributor
Contact Us