化合物信息

Description

Cancer

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

IC₅₀

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.

Features

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 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.

Animal Models

A549 xenografts in Athymic rats (RH-rnu/rnu)

Formulation

0.5% methylcellulose in distilled water

Doses

1 mg/kg

Administration

Oral administration