Tivozanib (AV-951)

Catalog No.S1207

Tivozanib (AV-951) is a potent and selective VEGFR inhibitor for VEGFR1/2/3 with IC50 of 30 nM/6.5 nM/15 nM, and also inhibits PDGFR and c-Kit, low activity observed against FGFR-1, Flt3, c-Met, EGFR and IGF-1R. Phase 3.

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Tivozanib (AV-951) Chemical Structure

Tivozanib (AV-951) Chemical Structure
Molecular Weight: 454.86

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  • Research Area
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  • Tivozanib (AV-951) Mechanism

Product Description

Biological Activity

Description Tivozanib (AV-951) is a potent and selective VEGFR inhibitor for VEGFR1/2/3 with IC50 of 30 nM/6.5 nM/15 nM, and also inhibits PDGFR and c-Kit, low activity observed against FGFR-1, Flt3, c-Met, EGFR and IGF-1R. Phase 3.
Targets VEGFR2 [1] VEGFR3 [1] EphB2 [1] VEGFR1 [1]

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IC50 6.5 nM 15 nM 24 nM 30 nM
In vitro AV-951 is a novel quinoline-urea derivative. AV-951 blocks VEGF-dependent activation of mitogen-activated protein kinases and proliferation of endothelial cells. [1]
In vivo In vivo studies show that AV-951 also decreases the micro vessel density and suppresses VEGFR2 phosphorylation levels in tumor xenografts, especially at a concentration of 1mg/kg (p.o. administration). AV-951 shows almost complete inhibition of tumor xenografts growth (TGI>85%) in athymic rats. [1] Another study in rat peritoneal disseminated tumor model shows that AV-951 could prolong the survival of the tumor-bearing rats with the MST of 53.5 days. AV-951 displays antitumor activity against many human tumor xenografts including lung, breast, colon, ovarian, pancreas and prostate cancer. [2]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

Kinase Assays Cell-free kinase assays are done in quadruplicate with 1 μM ATP to determine the IC50 values of AV-951 against a variety of recombinant receptor and nonreceptor tyrosine kinases including VEGFR1, VEGFR2, VEGFR3, c-Kit, PDGFRβ, Flt-3 and FGFR1.

Cell Assay: [1]

Cell lines Human umbilical vein endothelial cells (HUVEC) and normal human dermal fibroblasts
Concentrations 1 μM
Incubation Time 15 minutes
Method Human umbilical vein endothelial cells (HUVEC) and normal human dermal fibroblasts-based assays are done to determine the ability of AV-951 to inhibit ligand-dependent phosphorylation of tyrosine kinase receptors. The cells are starved overnight in appropriate basic medium containing 0.5% fetal bovine serum (FBS). The cells are incubated for 1 hour following the addition of AV-951 or 0.1% DMSO, and then stimulated with the cognate ligand at 37 °C. Receptor phosphorylation is induced for 5 minutes except for VEGFR3 (10 minutes), c-Met (10 minutes), and c-Kit (15 minutes). All the ligands used in the assays are human recombinant proteins, except for VEGF-C, a rat recombinant protein. Following cell lysis, receptors are immunoprecipitated with appropriate antibodies and subjected to immunoblotting with phosphotyrosine. Quantification of the blots and calculation of IC50 values are carried ou

Animal Study: [1]

Animal Models A549 xenografts in Athymic rats (RH-rnu/rnu)
Formulation 0.5% methylcellulose in distilled water
Dosages 1 mg/kg
Administration Oral administration

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] Nakamura K, et al. Cancer Res, 2006, 66(18), 9134-9142.

[2] Taguchi E, et al. Cancer Sci, 2008, 99(3), 623-630.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02627963 Recruiting Carcinoma, Renal Cell AVEO Pharmaceuticals, Inc. April 2016 Phase 3
NCT01972516 Terminated Ovarian Cancer|Fallopian Tube Cancer|Primary Peritoneal Carcinoma Dana-Farber Cancer Institute|National Comprehensive Cance  ...more Dana-Farber Cancer Institute|National Comprehensive Cancer Network|AVEO Pharmaceuticals, Inc. November 2013 Phase 2
NCT01728181 Withdrawn Non-small Cell Lung Cancer|Stage IV Disease|EGFR Unknown or Wild-type University of Utah November 2013 Phase 1|Phase 2
NCT01835223 Recruiting Advanced Adult Hepatocellular Carcinoma|Non-Resectable Hepatocellular Carcinoma Roswell Park Cancer Institute|National Comprehensive Canc  ...more Roswell Park Cancer Institute|National Comprehensive Cancer Network|AVEO Pharmaceuticals, Inc.|National Cancer Institute (NCI) July 2013 Phase 1|Phase 2
NCT01846871 Active, not recruiting Glioblastoma Massachusetts General Hospital|National Comprehensive Can  ...more Massachusetts General Hospital|National Comprehensive Cancer Network June 2013 Phase 2

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Chemical Information

Download Tivozanib (AV-951) SDF
Molecular Weight (MW) 454.86
Formula

C22H19ClN4O5

CAS No. 475108-18-0
Storage 3 years -20℃powder
2 years -80℃in solvent
Synonyms KRN-951
Solubility (25°C) * In vitro DMSO 20 mg/mL (43.96 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
In vivo 0.5% methylcellulose 30 mg/mL
* <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 1-(2-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-3-(5-methylisoxazol-3-yl)urea

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