Tivantinib (ARQ 197)

Catalog No.S2753

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

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Tivantinib (ARQ 197) Chemical Structure

Tivantinib (ARQ 197) Chemical Structure
Molecular Weight: 369.42

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Related Compound Libraries

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

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Product Information

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  • 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 in a cell-free assay, little activity to Ron, and no inhibition to EGFR, InsR, PDGFRα or FGFR1/4. Phase 3.
Targets c-Met [1]
(Cell-free assay)
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]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
MNK-45MYLLbY5ie2ViYYPzZZk>NUi2SXFqhjFyIN88US=>MkiybY5pcWKrdIOgZ{1O\XRicHjvd5Bpd3K7bHH0bY9vKGGwZDDkc5dve3S{ZXHtJIMuVWW2IIPp[45idGmwZzDwZZRpf2G7cx?=NXLUbm1{OjB2OESwNVg>
HT29NF\C[HZMcW6jc3WgZZN{[Xl?MUn+NVAh|ryPM2K1NIlvcGmkaYTzJIMuVWW2IIDoc5NxcG:{eXzheIlwdiCjbnSg[I94dnO2cnXhcUBkNU2ndDDzbYdv[WyrbnegdIF1cHejeYO=NF\qUJUzODR6NECxPC=>
MDA-MB-231NX65RoRJU2mwYYPlJIF{e2G7MYf+NVAh|ryPNFy3NndqdmirYnn0d{BkNU2ndDDwbI9{eGixconsZZRqd25iYX7kJIRwf26|dILlZY0h[y2PZYSgd4lodmGuaX7nJJBifGi5YYnzM4Sx[FIxPDh2MEG4
NCI-H441MYPLbY5ie2ViYYPzZZk>M{LQc54yOCEQvF2=NEDvU3FqdmirYnn0d{BkNU2ndDDwbI9{eGixconsZZRqd25iYX7kJIRwf26|dILlZY0h[y2PZYSgd4lodmGuaX7nJJBifGi5YYnzM1fi[|IxPDh2MEG4
SK-MEL-28M{DmTmdzd3e2aDDpcohq[mm2b4L5JIF{e2G7NXfIc3FuOzNizszNMYnJR|UxRjN|IN88US=>NIrRN|YzODR6NECxPC=>
NCI-H661NUjENlJoT3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm=NF;WZ5o{OyEQvF2=NXrFOI0xUUN3ME6zN{DPxE1?NXHHNnhPOjB2OESwNVg>
NCI-H446MVLHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>?NFnI[Iw{OyEQvF2=M2fIT2lEPTB;NzFOwG0>MnjaNlA1QDRyMUi=
MDA-MB-231MnP0S5Jwf3SqIHnubIljcXSxcomgZZN{[Xl?NFiwSpg{OyEQvF2=M3jnSGlEPTB;MD61OUDPxE1?NWC5VHFlOjB2OESwNVg>
DLD-1MUHHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>?NEf1fXQ{OyEQvF2=MnjiTWM2OD1yLkWzJO69VQ>?M4nIPVIxPDh2MEG4
A549M1\0U2dzd3e2aDDpcohq[mm2b4L5JIF{e2G7MoDMN|Mh|ryPNGHkXVFKSzVyPUCuOVkh|ryPNYToSXJvOjB2OESwNVg>
SK-OV-3NVewR4o6T3Kxd4ToJIlvcGmkaYTvdpkh[XO|YYm=NUO5PYtjOzNizszNNWPUOG9qUUN3ME2wMlY3KM7:TR?=NV:5VIt7OjB2OESwNVg>
NCI-H460NIfFTppIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=M{X2ZlM{KM7:TR?=MUHJR|UxRTBwNjFOwG0>NGqwfYszODR6NECxPC=>
A375M1\6dWdzd3e2aDDpcohq[mm2b4L5JIF{e2G7NHH5TIE{OyEQvF2=MXjJR|UxRTBwNEKg{txOMorpNlA1QDRyMUi=
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HT29NIj3[JVIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=NIXHfXk{OyEQvF2=MUnJR|UxRTBwNEmg{txOMoPKNlA1QDRyMUi=
MKN-45M2PzO2dzd3e2aDDpcohq[mm2b4L5JIF{e2G7NWK0U|F{OzNizszNNEHrTWtKSzVyPUCuOVgh|ryPNF;vN2MzODR6NECxPC=>
HT29NWTWem97SXCxcITvd4l{KGG|c3H5NEOyTZV,OTBizszNM{n6R5Nq\26rZnnjZY51dHliaX7keYNmeyCjcH;weI9{cXNiYomgPFAuQTBnLh?=NEj0ZYIzODR6NECxPC=>
MKN-45NH\CPJdCeG:ydH;zbZMh[XO|YYm=MnjYglExKM7:TR?=NXGwSFVJe2mpbnnmbYNidnSueTDpcoR2[2W|IHHwc5B1d3OrczDifUA5OC17MDWuMYOyNFQ5PDBzOB?=
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SNU638MoHSR5l1d3SxeHnjxsBie3OjeR?=MmjoglExKM7:TR?=MYXpcohq[mm2czD0bIUh[2WubDDndo94fGhwMYWyN|U6QDJ5Nh?=
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... Click to View More Cell Line Experimental Data

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

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

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
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 2016-07-23)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02608411 Recruiting Carcinoma, Small Cell Istituto Oncologico Veneto IRCCS October 2015 Phase 2
NCT02150733 Active, not 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 Active, not recruiting Colorectal Cancer Metastatic|C-met Overexpression Armando Santoro, MD|Istituto Clinico Humanitas March 2013 Phase 2
NCT02049060 Recruiting Malignant Pleural Mesothelioma|Nonsquamous Nonsmall Cell Neoplasm of Lung Armando Santoro, MD|Istituto Clinico Humanitas January 2013 Phase 1|Phase 2

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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 solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 73 mg/mL (197.6 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo
* <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

Customer Product Validation(1)


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Rating
Source PLoS One, 2014, 9(9): e105919. Tivantinib (ARQ 197) purchased from Selleck
Method Western Blot
Cell Lines H513 cells
Concentrations 0-0.5 μM
Incubation Time 48 h
Results The levels of cyclin D1, which is a G0/G1 cell cycle regulator were decreased in cells treated with ARQ 197, GDC-0980 or NVP-BEZ235, in a dose dependent manner. In the case of NVP-BEZ235 the effect was much more pronounced in H513 cells. The combinatorial treatment of ARQ 197/GDC-0980 and ARQ 197/NVP-BEZ235 however induced significant levels of cleaved PARP in both MPM cell lines. Individual treatment with GDC-0980 or NVP-BEZ235 had little effect as evidenced from cleaved PARP levels.

Tech Support

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.

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