product name Brivanib (BMS-540215)
Description: Brivanib is a potent and ATP-competitive inhibitor against VEGFR2 with IC50 of 25 nM, moderate potency against VEGFR-1 and FGFR-1, but >240-fold against PDGFR-β. Brivanib is the hydrolyzed form of Brivanib alaninate, which is a vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor with potential antineoplastic activity. Brivanib strongly binds to and inhibits VEGFR2, a tyrosine kinase receptor expressed almost exclusively on vascular endothelial cells; inhibition of VEGFR2 may result in inhibition of tumor angiogenesis, inhibition of tumor cell growth, and tumor regression.
References: J Med Chem. 2006 Apr 6;49(7):2143-6; Clin Cancer Res. 2008 Oct 1;14(19):6146-53.
370.38
Formula
C19H19FN4O3
CAS No.
649735-46-6
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 74 mg/mL (199.8 mM)
Water: <1 mg/mL
Ethanol: 3 mg/mL (8.1 mM)
Solubility (In vivo)
Synonyms
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19420761
| In Vitro |
In vitro 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. Kinase Assay: 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. Cell Assay: 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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| In Vivo | 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. |
| Animal model | H3396 xenografts in athymic mice |
| Formulation & Dosage | Dissolved in PEG400: Tween80 (75:25) (orally) or PEG400: water (3:2) (i.v.); 1mg/kg; oral gavage or i.v. |
| References | J Med Chem. 2006 Apr 6;49(7):2143-6; Clin Cancer Res. 2008 Oct 1;14(19):6146-53. |
