AV-951(Tivozanib)

• Catalog No.: S1207
• CAS Number: 475108-18-0
• M. F.: C22H19ClN4O5
• M. W.: 454.86306
• Storage: -20°C

SYNONYMS

• IUPAC name: 1-{2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-3-(5-methyl-1,2-oxazol-3-yl)urea
• IUPAC Traditional name: tivozanib
• Synonyms: Tivozanib

DATABASE IDS

• CAS Number: 475108-18-0

PROPERTIES

• Target: VEGFR
• Target: c-Kit
• Target: PDGFR
• Salt Data: Free Base
• Solubility: DMSO
• Storage Condition: -20°C

DETAILS

Description (English)

Research Area

• Description: Cancer

Biological Activity

• Description: AV-951 (Tivozanib, KRN-951) is a potent and selective VEGFR inhibitor for VEGFR1, VEGFR2 and VEGFR3 with IC50 of 0.21 nM, 0.16 nM and 0.24 nM, respectively.
• Targets: VEGFR1; VEGFR2; VEGFR3
• IC50: 0.21 nM; 0.16 nM; 0.24 nM ^[1]
• In Vitro: AV-951 is a novel quinoline-urea derivative. AV-951 inhibits phosphorylation of PDGFR? and c-Kit with IC50 of 1.72 and 1.63 nM, respectively. 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]
• Clinical Trials: AV-951 is currently in Phase II clinical trial in treatment of gastrointestinal cancer.

Protocol

• Protocol: 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.
• Protocol: Cell Assay ^[1]
• Cell Lines: Human umbilical vein endothelial cells (HUVEC) and normal human dermal fibroblasts
• Concentrations: 1 μM
• Incubation Time: 15 minutes
• Methods: 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.
• Protocol: Animal Study ^[1]
• Animal Models: A549 xenografts in Athymic rats (RH-rnu/rnu)
• Formulation: 0.5% methylcellulose in distilled water
• Doses: 1 mg/kg
• Administration: Oral administration

References

• References: [1] Nakamura K, et al. Cancer Res, 2006, 66(18), 9134-9142.
• References: [2] Taguchi E, et al. Cancer Sci, 2008, 99(3), 623-630.

REFERENCES

• Nakamura K, et al. Cancer Res, 2006, 66(18), 9134-9142.
• Taguchi E, et al. Cancer Sci, 2008, 99(3), 623-630.