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Tivozanib(AV951 KRN-951)
本产品不向个人销售,仅用作科学研究,不用于任何人体实验及非科研性质的动物实验。
Tivozanib(AV951 KRN-951)图片
CAS NO:475108-18-0
规格:≥98%
包装与价格:
包装价格(元)
2mg电议
5mg电议
10mg电议
25mg电议
50mg电议
100mg电议
250mg电议
500mg电议

产品介绍
理化性质和储存条件
Molecular Weight (MW)454.86
FormulaC22H19ClN4O5
CAS No.475108-18-0
Storage-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)DMSO: 20 mg/mL (43.96 mM)
Water: <1 mg/mL
Ethanol:<1 mg/mL
Solubility (In vivo)0.5% methylcellulose: 30 mg/mL
SynonymsTivozanib; KRN-951, AV-951; AV951; AV 951; KRN951; KRN 951

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

SMILES Code: O=C(NC1=NOC(C)=C1)NC2=CC=C(OC3=CC=NC4=CC(OC)=C(OC)C=C34)C=C2Cl

实验参考方法
In Vitro

In vitro activity: Tivozanib (AV-951) is a novel quinoline-urea derivative. AV-951 blocks VEGF-dependent activation of mitogen-activated protein kinases and proliferation of endothelial cells. Tivozanib potently inhibits VEGF-induced VEGFR2 phosphorylation in endothelial cells with IC50 of 0.16 nM. It also inhibits ligand-induced phosphorylation of PDGFRβ and c-Kit with IC50 of 1.72 and 1.63 nM, respectively. Tivozanib inhibits VEGF-mediated migration of human umbilical vein endothelial cells


Kinase Assay: 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: 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 out.

In VivoIn 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. 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.
Animal modelA549 xenografts in Athymic rats (RH-rnu/rnu)
Formulation & DosageFormulated in 0.5% methylcellulose in distilled water; 1mg/kg; oral gavage
ReferencesCancer Res. 2006 Sep 15;66(18):9134-42; Cancer Sci. 2008 Mar;99(3):623-30.
生物活性


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 (o) 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.