Tivozanib (AV-951)

Names

[ Name ]:
Tivozanib (AV-951)

[Synonym ]:
AV951
AV-951
Urea, N-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-N'-(5-methyl-3-isoxazolyl)-
N-(2-chloro-4-((6,7-dimethoxy-4-quinolyl)oxy)phenyl)-N'-(5-methyl-3-isoxazolyl)urea
Tivozanib
KRN-951
1-{2-Chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl}-3-(5-methyl-1,2-oxazol-3-yl)urea

Biological Activity

[Description]:

Tivozanib (AV-951; KRN951) is a highly potent and selective VEGFR 1/2/3 inhibitor with IC50s of 0.21, 0.16, and 0.24 nM in cell assay, respectively.

[Related Catalog]:

Research Areas >> Cancer

[Target]

VEGFR1:30 nM (IC50)

VEGFR2:6.5 nM (IC50)

VEGFR3:15 nM (IC50)

[In Vitro]

Tivozanib potently inhibits VEGF-induced VEGFR2 phosphorylation in endothelial cells (IC50=0.16 nM). It also inhibits ligand-induced phosphorylation of PDGFRβ and c-Kit (IC50=1.72 and 1.63 nM, respectively). Tivozanib blocks VEGF-dependent, but not VEGF-independent, activation of mitogenactivated protein kinases and proliferation of endothelial cells. It inhibits VEGF-mediated migration of human umbilical vein endothelial cells[1].

[In Vivo]

Following p.o. administration to athymic rats, Tivozanib decreases the microvessel density within tumor xenografts and attenuates VEGFR-2 phosphorylation levels in tumor endothelium. It also displays antitumor activity against a wide variety of human tumor xenografts, including lung, breast, colon, ovarian, pancreas, and prostate cancer[1].

[Kinase Assay]

Cell-free kinase assays are done in quadruplicate with 1 μM ATP to determine the IC50 values of KRN951 against a variety of recombinant receptor and nonreceptor tyrosine kinases[1].

[Cell Assay]

Cell-based assays are done to determine the ability of KRN951 to inhibit ligand-dependent phosphorylation of receptor tyrosine kinases. Briefly, the cells are starved overnight in appropriate basic medium containing 0.5% fetal bovine serum (FBS). Following the addition of KRN951 or 0.1% DMSO, the cells are incubated for 1 hour 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[1].

[Animal admin]

Mice: Cancer cells are s.c. inoculated into the right flank of the athymic rats. Once established, tumors of 1,500 mm3 are surgically excised and smaller tumor fragments (20-30 mg) are s.c. implanted in the right flank of irradiated rats. Oral administration of KRN951 (0.2 or 1 mg/kg) or vehicle is initiated at the day of randomization (day 0). Tumor volume is measured twice weekly with Vernier calipers, and calculated[1].

[References]

[1]. Nakamura K, et al. KRN951, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects functional vascular properties. Cancer Res. 2006 Sep 15;66(18):9134-42.

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.4±0.1 g/cm3

[ Boiling Point ]:
550.4±50.0 °C at 760 mmHg

[ Molecular Formula ]:
C₂₂H₁₉ClN₄O₅

[ Molecular Weight ]:
454.863

[ Flash Point ]:
286.7±30.1 °C

[ Exact Mass ]:
454.104401

[ PSA ]:
107.74000

[ LogP ]:
4.31

[ Vapour Pressure ]:
0.0±1.5 mmHg at 25°C

[ Index of Refraction ]:
1.680

[ Storage condition ]:
-20°C

Tivozanib (AV-951)

Names

Biological Activity

Chemical & Physical Properties

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream

Related Compounds