Brivanib (BMS-540215) 649735-46-6

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Molecular Weight:

370.38 Brivanib is an ATP-Competitive Inhibitor against VEGFR2 with IC50 of 25 nM, moderate potency against VEGFR-1 and FGFR-1, but >240-fold against PDGFR-β. Phase 3.


Biological Activity


Brivanib also inhibits VEGFR1 and FGFR-1 with IC50 of 0.38 μM and 0.148
μM. Brivanib is not sensitive to PDGFRβ, EGFR, LCK, PKCα or JAK-3 with
IC50 all above 1900 nM. Brivanib could inhibit the proliferation of
VEGF-stimulated HUVECs with IC50 of 40 nM, compared to 276 nM in
FGF-stimulated HUVECs. On the other hand, Brivanib exhibits low activity
to tumor cell lines.


Brivanib displays antitumor activities in H3396 xenograft in athymic
mice. At a dose of 60 and 90 mg/kg (p.o.), Brivanib completely inhibits
the tumor growth, with TGI of 85% and 97%, respectively. Moreover, Brivanib significantly suppresses tumor growth in
Hepatocellular carcinoma (HCC) xenografts, which due to the decrease in
phosphorylation of VEGFR2. The results show that the tumor weights in
06-0606 xenograft mice are 55% and 13%, compared with the controls at a
dose of 50 mg/kg and 100 mg/kg. Brivanib is suggested to be efficient in
treatment of HCC.






In Vitro Kinase Assays


Recombinant Proteins containing tyrosine kinases are expressed as GST
fusion proteins using baculovirus expression vector system in Sf9 cells.
All enzymes are stored at -80 °C. Brivanib is dissolved in DMSO and
diluted by water/10% DMSO. The VEGFR2 kinase solution is composed by 8
ng GST-VEGFR2 enzyme, 75 μg/mL substrate, 1 μM ATP, and 0.04 μCi [γ-33P]-ATP in 50 μL buffer: 20 mM Tris (pH 7.0), 25 μg/mL BSA, 1.5 mM MnCl2,
0.5 mM dithiothreitol).


Flk-1 kinase solution is composed by 10 ng
GST-Flk-1 enzyme, 75 μg/mL substrate, 1 μM ATP, and 0.04 μCi [γ-33P]-ATP in 50 μL buffer: 20 mM Tris, pH 7.0, 25 μg/mL BSA, 4 mM MnCl2,
0.5 mM dithiothreitol). The reactions are incubated for 1 hour at 27 °C
and terminated with cold trichloroacetic acid (TCA) to a final
concentration of 15%. These TCA precipitates are collected onto
unifilter plates and quantitated by liquid scintillation counter.

Method

The cells are stimulated by VEGF or FGF at a concentration of 8 or 80
ng/mL. These cells are seeded in 96 well plates at a density of 2 × 103 and incubated for 24 hours. Brivanib at various dilutions are added to the cells for another 48 hours. Then 0.5 μCi of [3H] thymidine is added for 24 hours. After that the incorporated tritium is quantified using a β-counter.

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Product Categories : Protein Tyrosine Kinase > VEGFR Inhibitor