| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| Other Sizes |
| Targets |
(Rac)-Tivantinib primarily targets the c-Met receptor tyrosine kinase (also known as HGFR) through a non-ATP competitive mechanism with a Ki of 355 nM. It inhibits both constitutive and ligand-mediated c-Met autophosphorylation. Additional studies have identified tubulin as a secondary target, as the compound disrupts microtubule dynamics and shows cytotoxic activity independent of cellular c-MET status. It also inhibits glycogen synthase kinase 3 alpha and beta (GSK3alpha/beta) in lung cancer cells, indicating a multi-targeted mechanism beyond c-Met inhibition alone.
|
|---|---|
| ln Vitro |
In vitro, (Rac)-Tivantinib inhibits c-Met phosphorylation in HT29, MKN-45 (IC50 100-300 nM), MDA-MB-231, and NCI-H441 cells. It suppresses proliferation of A549 (IC50 0.38 microM), DBTGR (IC50 0.45 microM), and NCI-H441 (IC50 0.29 microM) cells. The compound reduces phosphorylation in the MAPK signaling cascade, prevents invasion and migration, and induces caspase-dependent apoptosis in c-Met-expressing cancer cells. Treatment leads to decreased Vmax of c-Met without affecting ATP's Km, confirming non-competitive inhibition and high kinase selectivity.
|
| ln Vivo |
In vivo, oral administration of (Rac)-Tivantinib (200 mg/kg) in HT29, MKN-45, and MDA-MB-231 xenograft models reduces tumor growth by 66%, 45%, and 79%, respectively, without significant body weight changes. A single oral dose leads to strong decrease in c-Met auto-phosphorylation after 24 hours. The compound inhibits growth of c-Met-dependent human tumor xenografts and has been evaluated in phase 3 clinical trials for various cancers, showing encouraging antitumor activity in phase 2 studies for hepatocellular carcinoma.
|
| Enzyme Assay |
Kinase assay protocol: Recombinant c-Met protein (100 ng) is preincubated with increasing concentrations of test compound for 30 minutes at room temperature. After preincubation, 100 microM of poly-Glu-Tyr substrate and various concentrations of ATP containing 5 microM [gamma-32P]ATP are added. The reaction is incubated for 5 minutes at room temperature, then stopped with 5 microL SDS sample buffer. Samples are loaded onto 7.5% acrylamide gel for SDS-PAGE, and phosphorylated substrates are visualized and quantified.
|
| Cell Assay |
Cell viability protocol: Human cancer cells (e.g., HT29, MKN-45, A549, NCI-H441) are seeded in culture medium and treated with increasing concentrations of (Rac)-Tivantinib (range 0-10 microM) for 72 hours. Cell viability is assessed using standard assays such as MTT, CellTiter-Glo, or crystal violet staining. IC50 values are calculated by nonlinear regression analysis of dose-response curves. For apoptosis assessment, cells are stained with annexin V-FITC/propidium iodide and analyzed by flow cytometry after 48 hours of treatment.
|
| Animal Protocol |
Animal xenograft protocol: Female athymic nude mice bearing established subcutaneous tumor xenografts (HT29, MKN-45, or MDA-MB-231, approximately 100-200 mm3) are randomized and treated with (Rac)-Tivantinib orally at 200 mg/kg daily or vehicle control. Tumor volumes are measured twice weekly using calipers, and body weights are recorded. At study endpoint (e.g., day 21-28), tumors are harvested for c-Met phosphorylation analysis by Western blot and immunohistochemistry.
|
| ADME/Pharmacokinetics |
(Rac)-Tivantinib demonstrates oral bioavailability and favorable pharmacokinetic properties. Following oral administration of 200 mg/kg in xenograft models, the compound achieves sufficient systemic exposure to maintain inhibition of c-Met phosphorylation for up to 24 hours post-dose. The racemic mixture shows similar absorption and distribution characteristics to the active enantiomer. Pharmacokinetic parameters include moderate clearance and volume of distribution consistent with small molecule kinase inhibitors.
|
| Toxicity/Toxicokinetics |
Preclinical toxicology evaluation indicates that (Rac)-Tivantinib is well-tolerated at efficacious doses in animal models, with no significant body weight changes observed following repeated oral dosing at 200 mg/kg in xenograft studies. Phase 1 clinical trials have shown an acceptable safety profile with common adverse events including fatigue, nausea, and anemia. No treatment-related serious adverse events leading to withdrawal were reported in early-phase studies.
|
| References |
|
| Additional Infomation |
(Rac)-Tivantinib (ARQ 197) was under clinical development as a potential anticancer agent, with phase 3 trials conducted for hepatocellular carcinoma and other solid tumors. However, subsequent studies revealed that its antitumor activity may involve off-target mechanisms including tubulin binding, challenging the initial selective c-Met inhibitor classification. The compound is now used primarily as a research tool for studying both c-Met-dependent and -independent mechanisms. Not approved for clinical use.
|
| Molecular Formula |
C23H19N3O2
|
|---|---|
| Molecular Weight |
369.42
|
| Exact Mass |
369.147
|
| CAS # |
1239986-50-5
|
| Related CAS # |
Tivantinib;905854-02-6;(3S,4S)-Tivantinib;905854-03-7;(rel)-Tivantinib;905853-99-8
|
| PubChem CID |
57355660
|
| Appearance |
Off-white to pink solid powder
|
| Density |
1.5±0.1 g/cm3
|
| Boiling Point |
716.0±60.0 °C at 760 mmHg
|
| Flash Point |
386.8±32.9 °C
|
| Vapour Pressure |
0.0±2.3 mmHg at 25°C
|
| Index of Refraction |
1.797
|
| LogP |
3.26
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
2
|
| Rotatable Bond Count |
2
|
| Heavy Atom Count |
28
|
| Complexity |
666
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
C1CC2=C3C(=CC=C2)C(=CN3C1)C4C(C(=O)NC4=O)C5=CNC6=CC=CC=C65
|
| InChi Key |
UCEQXRCJXIVODC-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C23H19N3O2/c27-22-19(16-11-24-18-9-2-1-7-14(16)18)20(23(28)25-22)17-12-26-10-4-6-13-5-3-8-15(17)21(13)26/h1-3,5,7-9,11-12,19-20,24H,4,6,10H2,(H,25,27,28)
|
| Chemical Name |
3-(1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-3-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
|
|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
