Tivantinib

SKU: orb1301058

Description

Tivantinib (ARQ 197) is an orally administered small molecule that selectively inhibits the c-Met receptor tyrosine kinase. It has demonstrated antineoplastic activity in preclinical studies, showing efficacy in both in vitro cell proliferation assays and in vivo xenograft models of various cancers, including hepatocellular and non-small cell lung carcinomas.

Research Area

Cell Biology, Signal Transduction

Key Properties

• CAS Number: 905854-02-6
• MW: 369.42
• Purity: 99.95%
• Formula: C₂₃H₁₉N₃O₂
• SMILES: O=C1NC(=O)[C@H]([C@@H]1c1c[nH]c2ccccc12)c1cn2CCCc3cccc1c23
• Target: c-Met/HGFR,Apoptosis
• Solubility: 10% DMSO+40% PEG300+5% Tween 80+45% Saline:2 mg/mL (5.41 mM);DMSO:125 mg/mL (338.37 mM);H2O:< 1 mg/mL (insoluble or slightly soluble);Ethanol:< 1 mg/mL (insoluble or slightly soluble)

Bioactivity

• Target IC50:
  c-Met:0.355 μM(Ki)
• In Vivo:
  ARQ-197 exhibits antitumor activity by inhibiting the proliferation of A549, DBTRG, and NCI-H441 cells, with IC50 values of 0.38, 0.45, and 0.29 μM respectively. Treatment with ARQ-197 reduces phosphorylation in the MAPK signaling cascade, thereby preventing invasion and migration. Moreover, ectopic expression of c-Met in the NCI-H661 cell line, which lacks endogenous c-Met expression, leads to an invasive phenotype that is inhibited by ARQ-197. This compound also inhibits human recombinant c-Met with a constant Ki value of 355 nM and blocks downstream c-Met signaling pathways by inhibiting c-Met phosphorylation. Despite increased concentrations of ARQ-197 not significantly affecting the Km of ATP, exposure to 0.5 μM ARQ-197 results in a threefold decrease in the Vmax of c-Met. The decrease in Vmax without affecting ATP's Km suggests ARQ-197 inhibits c-Met through a non-ATP competitive mechanism, indicating high kinase selectivity. ARQ-197 suppresses both constitutive and ligand-mediated c-Met autophosphorylation, thereby inhibiting c-Met activity and downstream effectors. In human cancer cells expressing c-Met, including HT29, MKN-45, and MDA-MB-231, ARQ-197 induces an increase in caspase-dependent apoptosis.
• In Vitro:
  Treatment with ARQ-197 across three heterotrophic transplantation models demonstrated a reduction in tumor growth: 66% in the HT29 model, 45% in the MKN-45 model, and 79% in the MDA-MB-231 model. Oral administration of 200 mg/kg ARQ-197 in these HT29, MKN-45, and MDA-MB-231 xenograft models did not result in significant weight changes. Pharmacologically, ARQ-197 notably inhibited the phosphorylation of c-Met in the human colon xenograft tumor HT29. A single oral dose of 200 mg/kg ARQ-197 led to a strong decrease in c-Met auto-phosphorylation after 24 hours. In summary, ARQ-197 inhibits the growth of c-Met-dependent human tumor xenografts.
• Cell Research:
  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.(Only for Reference)

Storage & Handling

• Storage: Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice/Shipping at ambient temperature.
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

c-Met/HGFR, cMet, c-Met, cMet/HGFR, Apoptosis, ARQ 197, ARQ197, ARQ-197, HGFR, Inhibitor, inhibit, Tivantinib

Compound Identifiers

PubChem CID

11494412