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Research Area
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Description
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Cancer |
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Biological Activity
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Description
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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. |
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Targets
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VEGFR1 |
VEGFR2 |
VEGFR3 |
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IC50 |
0.21 nM |
0.16 nM |
0.24 nM [1] |
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In Vitro
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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] |
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In Vivo
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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] |
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Clinical Trials
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AV-951 is currently in Phase II clinical trial in treatment of gastrointestinal cancer. |
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Features
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Protocol
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Kinase Assay
[1]
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| 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. |
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Cell Assay
[1]
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| 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. |
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Animal Study
[1]
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| Animal Models |
A549 xenografts in Athymic rats (RH-rnu/rnu) |
| Formulation |
0.5% methylcellulose in distilled water |
| Doses |
1 mg/kg |
| Administration |
Oral administration |
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