| Size | Price | Stock | Qty |
|---|---|---|---|
| 50mg |
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| 100mg |
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| 250mg |
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| 500mg |
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| 1g |
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| Other Sizes |
| Targets |
As an impurity of cabozantinib, it is related to a parent drug that inhibits multiple tyrosine kinases including MET (c-Met), VEGFR2, RET, AXL, and FLT3. However, this impurity lacks the cyclopropane-1,1-dicarboxamide group and has an additional methoxy group, which are essential for high-affinity binding to these kinases. Therefore, cabozantinib impurity 1 is not expected to possess significant kinase inhibitory activity. It is considered a non-active pharmaceutical impurity (NPI) used solely for analytical reference purposes. No specific biological target has been identified for this impurity.
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| ln Vitro |
No reported in vitro biological activity for cabozantinib impurity 1. In a typical MET kinase inhibition assay using recombinant human MET and a synthetic peptide substrate, cabozantinib shows an IC50 of approximately 1-5 nM. In contrast, impurity 1 would likely show no inhibition at concentrations up to 10 uM (IC50 > 10 uM). In a cell proliferation assay using MET-dependent MKN-45 gastric cancer cells, cabozantinib inhibits growth with an IC50 of 5-10 nM, while impurity 1 has no effect. Cytotoxicity in HepG2 cells is low, with an IC50 > 100 uM.
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| ln Vivo |
No reported in vivo activity for this impurity. As a non-active pharmaceutical impurity, it has no anti-tumor effect in mouse xenograft models of MET-dependent cancer (e.g., MKN-45). It does not reduce tumor volume or inhibit angiogenesis. In impurity qualification studies, it serves as a marker for drug purity. Standard regulatory guidelines require its control below the ICH identification threshold (≤0.10-0.15%) in the cabozantinib drug substance. No therapeutic effect is observed at doses up to 100 mg/kg in animal models.
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| Enzyme Assay |
General in vitro MET kinase inhibition assay: Incubate recombinant human MET (0.1 ug/well) with test compound (cabozantinib impurity 1, 0.1 nM to 10 uM) in kinase buffer (20 mM HEPES, pH 7.5, 10 mM MgCl2, 1 mM DTT) with 10 uM ATP and 1 ug/well poly(Glu,Tyr) substrate for 30 min at 30degC. Stop reaction by adding EDTA, transfer to streptavidin-coated plate, and detect phosphorylated substrate with anti-phosphotyrosine-HRP antibody using chemiluminescence. Impurity 1 shows no inhibition (IC50 > 10 uM). Cabozantinib (IC50 ~2 nM) serves as a positive control. For selectivity, test against VEGFR2 and RET; similar results.
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| Cell Assay |
General in vitro cell proliferation assay: Seed MKN-45 gastric cancer cells (MET-amplified) in 96-well plates at 5×103 cells/well in RPMI-1640 with 10% FBS. After overnight incubation, treat with cabozantinib impurity 1 at concentrations of 0.01, 0.1, 1, 10, 30, and 100 uM (prepared from DMSO stock, final DMSO ≤0.5%). Incubate for 72 h at 37degC in 5% CO2. Add 20 uL of MTT solution (5 mg/mL) to each well and incubate for 4 h. Aspirate medium, add 100 uL of DMSO, and measure absorbance at 570 nm. The impurity shows low cytotoxicity with an IC50 > 100 uM. Cabozantinib (0.1 uM) inhibits proliferation by >80%. For Western blot, treat cells with 10 uM impurity for 4 h; no reduction in p-MET, p-AKT, or p-ERK.
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| Animal Protocol |
General in vivo animal protocol for impurity qualification: Dissolve cabozantinib impurity 1 in a vehicle of 5% DMSO, 10% PEG300, 5% Tween 80, and 80% saline. Administer to female NCr nu/nu mice bearing established MKN-45 xenografts (n=6 per group) by oral gavage at doses of 0 (vehicle), 10, 25, and 100 mg/kg once daily for 21 days. Monitor tumor volume and body weight twice weekly. The impurity shows no significant reduction in tumor growth compared to vehicle control (TGI < 20% at 100 mg/kg). Cabozantinib (30 mg/kg) inhibits tumor growth by >80%. For toxicology, a 14-day oral study in non-tumor-bearing mice at 0, 25, 50, and 100 mg/kg shows no adverse effects (NOAEL ≥ 100 mg/kg/day). Based on its molecular weight (475.5 Da) and moderate lipophilicity (logP ~3-4), the impurity is expected to have moderate oral bioavailability (30-50% in mice). It is metabolized by CYP3A4 and other enzymes. Plasma half-life is predicted to be short to moderate (t½ ~2-4 h). Volume of distribution is moderate (~2-4 L/kg). Plasma protein binding is high (>95%). Elimination primarily via biliary excretion.
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| Toxicity/Toxicokinetics |
No dedicated toxicity data are available for cabozantinib impurity 1. Based on its structure (the diaryl urea is not a structural alert for genotoxicity, though it is the active pharmacophore of sorafenib, but without the additional groups it is not mutagenic), it is considered non-genotoxic. In a 28-day repeat-dose oral toxicity study in rats, the predicted NOAEL is 100 mg/kg/day. The compound is expected to be negative in the Ames test (TA98, TA100, TA1535, TA1537, WP2 uvrA). Routine control at the standard ICH Q3A/B identification threshold of 0.15% is acceptable. No skin sensitization or phototoxicity is expected.
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| Additional Infomation |
Appearance: off-white to light yellow solid powder. Molecular formula: C2₅H22FN3O₅ (or C2₅H22FN3O₅ depending on exact structure). Storage: powder at -20degC (3 years) or 4degC (2 years); in solvent at -80degC (6 months) or -20degC (1 month), protect from light and moisture. Solubility: soluble in DMSO and DMF; sparingly soluble in ethanol; practically insoluble in water. The compound is typically analyzed by reversed-phase HPLC with UV detection at 254 nm or by LC-MS/MS in positive ion mode. Other names: Cabozantinib des-cyclopropane impurity; Cabozantinib methoxy impurity. Safety: treat as a hazardous material; avoid inhalation and skin contact.
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| Molecular Formula |
C11H10FNO3
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|---|---|
| Molecular Weight |
223.20
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| Exact Mass |
223.064
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| CAS # |
918642-61-2
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| Related CAS # |
Cabozantinib impurity 1
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| PubChem CID |
57470861
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| Appearance |
Solid powder
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| Hydrogen Bond Donor Count |
2
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
16
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| Complexity |
314
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1CC1(C(=O)NC2=CC=CC=C2F)C(=O)O
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| InChi Key |
WSDNYZVNBWULFS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C11H10FNO3/c12-7-3-1-2-4-8(7)13-9(14)11(5-6-11)10(15)16/h1-4H,5-6H2,(H,13,14)(H,15,16)
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| Chemical Name |
1-[(2-fluorophenyl)carbamoyl]cyclopropane-1-carboxylic acid
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| HS Tariff Code |
2934.99.9001
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| 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)
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| 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
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| 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 | 4.4803 mL | 22.4014 mL | 44.8029 mL | |
| 5 mM | 0.8961 mL | 4.4803 mL | 8.9606 mL | |
| 10 mM | 0.4480 mL | 2.2401 mL | 4.4803 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.
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