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Purity: =99.15%
Tivozanib (formerly KRN951 or AV-951; brand name Fotivda) is a novel, orally bioavailable, potent and selective inhibitor of VEGFR (vascular endothelial growth factor receptors) with potential antineoplastic activity. With IC50s of 30 nM/6.5 nM/15 nM, it inhibits VEGFR1/2/3. For the treatment of advanced renal cell carcinoma (RCC) that has relapsed or is refractory, tivozanib was approved by the US FDA in March 2021 and the European Medicines Agency (EMA) in August 2017. When tivozanib binds to and inhibits VEGFRs 1, 2, and 3, it may also inhibit tumor angiogenesis, endothelial cell migration and proliferation, and tumor cell death. By inducing proangiogenic signaling in endothelial cells through VEGF receptor (VEGFR) tyrosine kinases, VEGF plays a crucial role in tumor angiogenesis. Consequently, Tivozanib has the potential to be used as an anticancer agent and VEGFRs are an appealing therapeutic target for cancer treatment.
| Targets |
VEGFR2 (IC50 = 6.5 nM); VEGFR3 (IC50 = 15 nM); EphB2 (IC50 = 24 nM); VEGFR1 (IC50 = 30 nM); PDGFRα (IC50 = 40 nM)
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| ln Vitro |
AV-951 is a novel derivative of urea and quinoline. AV-951 prevents endothelial cell proliferation and the VEGF-dependent activation of mitogen-activated protein kinases.[1]
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| ln Vivo |
Studies conducted in vivo demonstrate that AV-951, particularly when administered orally at a dose of 1 mg/kg, also reduces micro vessel density and suppresses VEGFR2 phosphorylation levels in tumor xenografts. In athymic rats, AV-951 almost completely inhibits the growth of tumor xenografts (TGI>85%).[1] Another study using a peritoneal disseminated tumor model in rats demonstrates that AV-951 can extend the survival of the tumor-bearing rats up to 53.5 days after the MST. When applied to various human tumor xenografts, such as lung, breast, colon, ovarian, pancreatic, and prostate cancer, AV-951 exhibits antitumor activity.[2]
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| Enzyme Assay |
The IC50 values of AV-951 against various recombinant receptor and nonreceptor tyrosine kinases, such as VEGFR1, VEGFR2, VEGFR3, c-Kit, PDGFRβ, Flt-3, and FGFR1, are ascertained by conducting cell-free kinase assays in quadruplicate using 1 μM ATP.
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| Cell Assay |
The ability of AV-951 to inhibit ligand-dependent phosphorylation of tyrosine kinase receptors is assessed using assays based on human umbilical vein endothelial cells (HUVEC) and normal human dermal fibroblasts. In the proper basic medium with 0.5% fetal bovine serum (FBS), the cells are starved for the duration of the next day. The cells are stimulated with the cognate ligand at 37 °C after being incubated for an hour with either AV-951 or 0.1% DMSO. With the exception of VEGFR3, c-Met, and c-Kit, which are induced for 10 and 15 minutes, respectively, receptor phosphorylation lasts for five minutes. VEGF-C, a rat recombinant protein, is the only ligand utilized in the assays that is not a human recombinant protein. After cell lysis, receptors are phosphotyrosine-immunoblotted after being immunoprecipitated with the proper antibodies. Both the blot quantification and IC50 value computation are completed.
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| Animal Protocol |
Mice: The athymic rats receive a subcutaneous injection of cancer cells in their right flank. Tumors up to 1,500 mm3 are surgically removed, and smaller pieces (20–30 mg) are s.c. implanted into the right flank of rats exposed to radiation. Beginning on day zero of randomization, oral administration of KRN951 (0.2 or 1 mg/kg) or the vehicle is administered. Using Vernier calipers, tumor volume is measured and computed twice a week.
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| References |
| Molecular Formula |
C22H19CLN4O5
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|---|---|
| Molecular Weight |
454.86
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| Exact Mass |
454.10
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| Elemental Analysis |
C, 58.09; H, 4.21; Cl, 7.79; N, 12.32; O, 17.59
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| CAS # |
475108-18-0
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| Related CAS # |
Tivozanib hydrochloride hydrate;682745-41-1
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| Appearance |
Solid powder
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| SMILES |
CC1=CC(=NO1)NC(=O)NC2=C(C=C(C=C2)OC3=C4C=C(C(=CC4=NC=C3)OC)OC)Cl
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| InChi Key |
SPMVMDHWKHCIDT-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H19ClN4O5/c1-12-8-21(27-32-12)26-22(28)25-16-5-4-13(9-15(16)23)31-18-6-7-24-17-11-20(30-3)19(29-2)10-14(17)18/h4-11H,1-3H3,(H2,25,26,27,28)
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| Chemical Name |
1-[2-chloro-4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-3-(5-methyl-1,2-oxazol-3-yl)urea
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| Synonyms |
Tivozanib; KRN-951, AV-951; AV951; AV 951; KRN951; KRN 951
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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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.50 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.50 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: 0.5% methylcellulose: 30mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1985 mL | 10.9924 mL | 21.9848 mL | |
| 5 mM | 0.4397 mL | 2.1985 mL | 4.3970 mL | |
| 10 mM | 0.2198 mL | 1.0992 mL | 2.1985 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04987203 | Active Recruiting |
Drug: Tivozanib Drug: Nivolumab |
Renal Cell Carcinoma | AVEO Pharmaceuticals, Inc. | September 9, 2021 | Phase 3 |
| NCT01885949 | Active Recruiting |
Drug: Tivozanib Drug: Enzalutamide |
Prostate Cancer | Massachusetts General Hospital | September 3, 2013 | Phase 2 |
| NCT04645160 | Recruiting | Drug: Tivozanib | Cholangiocarcinoma Bile Duct Neoplasm |
National Cancer Institute (NCI) |
March 4, 2022 | Phase 1 Phase 2 |
| NCT06053658 | Not yet recruiting | Drug: Tivozanib Drug: Nivolumab |
Renal Cell Carcinoma | M.D. Anderson Cancer Center | January 31, 2024 | Phase 2 |
| NCT05000294 | Recruiting | Drug: Tivozanib Drug: Atezolizumab |
Bile Duct Cancer Breast Cancer |
University of Florida | November 3, 2021 | Phase 1 Phase 2 |
Effects of KRN951 on VEGFR-2 phosphorylation levels on tumor endothelium and tumor microvessel density.Cancer Res.2006 Sep 15;66(18):9134-42. |
DCE-MRI analysis of tumor vascular permeability. Athymic rats bearing Calu-6 tumors were randomized at day −1 and then treated with 0.2 mg/kg KRN951 (○), 1 mg/kg KRN951 (▴), or vehicle (•) once daily for 14 days (days 0-13).Cancer Res.2006 Sep 15;66(18):9134-42. |
Effects of KRN951 on tumor vessel diameter and pericyte coverage.Cancer Res.2006 Sep 15;66(18):9134-42. |
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