Semaxanib (SU5416) 194413-58-6

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Molecular Weight:

238.28 Semaxanib (SU5416) is a potent and selective VEGFR(Flk-1/KDR) inhibitor with IC50 of 1.23 μM, 20-fold more selective for VEGFR than PDGFRβ, lack of activity against EGFR, InsR and FGFR. Phase 3.


Biological Activity


Semaxanib inhibits VEGF-dependent phosphorylation of the Flk-1 receptor
in Flk-1-overexpressing NIH 3T3 cells with IC50 of 1.04 μM. Semaxanib
inhibits PDGF-dependent autophosphorylation in NIH 3T3 cells with IC50
of 20.3 μM. Semaxanib inhibits VEGF- and FGF-driven mitogenesis in a
dose-dependent manner with IC50 of 0.04 and 50 μM, respectively.
Semaxanib treatment has no effect on the in vitro growth of C6 glioma,
Calu 6 lung carcinoma, A375 melanoma, A431 epidermoid carcinoma, and
SF767T glioma cells (all IC50s > 20 μM).


Semaxanib dose-related inhibits growth of A375 tumor in vivo. A >85%
inhibition of subcutaneous tumor growth is observed with daily i.p.
administration of SU5416 in DMSO at Semaxanib, without measurable
toxicity. Semaxanib shows broad spectrum antitumor activity.


SU5416
significantly inhibits the subcutaneous growth of 8 of 10 tumor lines
tested (A431, Calu-6, C6, LNCAP, EPH4-VEGF, 3T3HER2, 488G2M2 and SF763T
cells) with an average mortality rate of 2.5%. Semaxanib
(25 mg/kg/day) displays potent antiangiogenic activity, resulting in a
significant reduction of both the total and functional vascular density
of the tumor microvasculature.






Biochemical kinase assays


Solubilized membranes from 3T3 Flk-1 cells are added to polystyrene
ELISA plates that had been precoated with a monoclonal antibody that
recognizes Flk-1. After an overnight incubation with lysate at 4 ℃,
serial dilutions of SU5416 are added to the immunolocalized receptor. To
induce autophosphorylation of the receptor, various concentrations of
ATP are added to the ELISA plate wells containing serially diluted
solutions of SU5416. The autophosphorylation is allowed to proceed for
60 min at room temperature and then stopped with EDTA.


The amount of
phosphotyrosine present on the Flk-1 receptors in the individual wells
is determined by incubating the immunolocalized receptor with a
biotinylated monoclonal antibody directed against phosphotyrosine. After
removal of the unbound anti-phosphotyrosine antibody, avidin-conjugated
horseradish pero-idase H is added to the wells. A stabilized form of
3,3 9,5,5 9-tetramethyl benzidine dihydrochloride and H2O2 is added to the wells. The color readout of the assay is allowed to develop for 30 min, and the reaction is stopped with H2SO4.

Method

HUVECs are plated in 96-well, flat-bottomed plates (1×104 cells/100 μL/well) in F-12K media containing 0.5% heat-inactivated FBS
and cultured at 37 ℃ for 24 h to quiesce the cells. Serial dilutions of
compounds prepared in medium containing 1% DMSO are then added for 2 h,
followed by the addition of mitogenic concentrations of either VEGF at 5
ng/mL or 20 ng/mL or acidic fibroblast growth factor at 0.25–5 ng/mL
in media.


The final concentration of DMSO in the assay is 0.25%. After
24 h, either [3H]thymidine (1 μCi/well) or BrdUrd is added, and the cell monolayers are incubated for another 24 h. The uptake of either [3H]thymidine or BrdUrd into cells is quantitated using a liquid scintillation counter or a BrdUrd ELISA, respectively.

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Product Categories : Protein Tyrosine Kinase > VEGFR Inhibitor