Tivozanib (AV-951)

 

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	VEGFR1/2/3	PDGFR-α/β	c-Kit	EphB2	Tie2
IC50	30 nM/6.5 nM/15 nM	40 nM/49 nM	78 nM	24 nM	78 nM [1]
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)
Dosages	1 mg/kg
Administration	Oral administration
Solubility	0.5% methylcellulose, 30 mg/mL

1

References

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number	Recruitment	Conditions	Sponsor /Collaborators	Start Date	Phases
NCT01835223	Not yet recruiting	Adult Primary Hepatocellular Carcinoma|Advanced Adult Primary Liver Cancer|Localized Unresectable Adult Primary Liver Cancer|Recurrent Adult Primary Liver Cancer	Roswell Park Cancer Institute|National Cancer Institute (NCI)	2013-04	Phase 2
NCT01853644	Not yet recruiting	Recurrent Epithelial Ovarian Cancer|Recurrent Fallopian Tube Cancer|Recurrent Primary Peritoneal Cancer	Northwestern University|National Comprehensive Cancer Network	2013-05	Phase 2
NCT01834183	Not yet recruiting	Renal Cell Carcinoma	Dana-Farber Cancer Institute	2013-06	Phase 2
NCT01846871	Not yet recruiting	Glioblastoma	Massachusetts General Hospital	2013-06	Phase 2
NCT01728181	Not yet recruiting	Non-small Cell Lung Cancer|Stage IV Disease|EGFR Unknown or Wild-type	University of Utah	2013-11	Phase 1|Phase 2

Chemical Information

Download Tivozanib (AV-951) SDF

Chemical Name	1-(2-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-3-(5-methylisoxazol-3-yl)urea

Preparing Stock Solutions

Stock Solution (1ml DMSO)	1mM	10mM	20mM	30mM
Mass(mg)	0.45486	4.5486	9.0972	13.6458

Customer Reviews (2)

Click to enlarge	Rating
	Source	Tivozanib (AV-951) purchased from Selleck
	Method	MTT Assay
	Cell Lines	HEK293 cells
	Concentrations	2.5-10 μM
	Incubation Time
	Results	Reversal effect of Tivozanib on the sensitivity of HEK/ABCB1 cells to vincrstine.

Product Citations (2)

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  Berberine Suppresses TPA-Induced Fibronectin Expression through the Inhibition of VEGF Secretion in Breast Cancer Cells [Kim S, et al. Cell Physiol Biochem 2013;32(5):1541-50]

  
  PubMed: 24335179


• 
  

  Antiangiogenic effects of tivozanib, an oral VEGF receptor tyrosine kinase inhibitor, on experimental choroidal neovascularization in mice. [Kang S, et al. Exp Eye Res 2013;112:125-33]

  
  PubMed: 23701975