Brivanib (BMS-540215)

370, 38

H3396 xenografts in athymic mice

Combining with best supportive care to placebo, Brivanib is currently in Phase III clinical trial in Asian subjects with advanced hepatocellular carcinoma (HCC) who have failed or are intolerant to sorafenib.

60 mg/kg (orally) or 10 mg/kg (intravenously)

25 nM, 25 nM, 25 nM, 25 nM, 25 nM, 25 nM

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. [1] 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. [2]

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 ug/mL substrate, 1 uM ATP, and 0.04 uCi [gamma-33P]-ATP in 50 uL buffer: 20 mM Tris (pH 7.0), 25 ug/mL BSA, 1.5 mM MnCl2, 0.5 mM dithiothreitol). Flk-1 kinase solution is composed by 10 ng GST-Flk-1 enzyme, 75 ug/mL substrate, 1 uM ATP, and 0.04 uCi [gamma-33P]-ATP in 50 uL buffer: 20 mM Tris, pH 7.0, 25 ug/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.

DMSO 74 mg/mL, Water <1 mg/mL, Ethanol 3 mg/mL

(R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[1, 2-f][1, 2, 4]triazin-6-yloxy)propan-2-ol