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Purity: ≥98%
Brivanib (formerly BMS-540215; BMS540215) is a novel, investigational, oral and ATP-competitive VEGFR2 inhibitor that may have anticancer effects. It exhibits moderate potency against VEGFR-1 and FGFR-1, but >240-fold against PDGFR-β. It inhibits VEGFR2 with an IC50 of 25 nM. In H3396 xenografts in athymic mice, it shows strong in vivo antitumor efficacy and outstanding anti-proliferative activity in vitro.
| Targets |
VEGFR2 (IC50 = 25 nM); Flk1 (IC50 = 89 nM); FGFR1 (IC50 = 148 nM); VEGFR1 (IC50 = 380 nM)
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|---|---|
| ln Vitro |
Brivanib also inhibits VEGFR1 and FGFR-1 with IC50 of 0.38 μM and 0.148 μM. Brivanib exhibits no sensitivity to PDGFRβ, EGFR, LCK, PKCα, or JAK-3, with all of their IC50 values above 1900 nM. With an IC50 of 40 nM for VEGF-stimulated HUVECs and 276 nM for FGF-stimulated HUVECs, brivanib was able to inhibit HUVEC proliferation. However, Brivanib shows minimal activity against tumor cell lines.[1]
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| ln Vivo |
Brivanib exhibits antitumor properties in athymic mice using an H3396 xenograft. Brivanib completely inhibits the growth of tumors at doses of 60 and 90 mg/kg (p.o.), with TGI of 85% and 97%, respectively.[1] Furthermore, Brivanib significantly inhibits the growth of tumors in xenografts of hepatocellular carcinoma (HCC), a phenomenon that is attributed to a decrease in VEGFR2 phosphorylation. In comparison to the controls at 50 mg/kg and 100 mg/kg, the tumor weights in the 06-0606 xenograft mice are 55% and 13%, respectively, according to the results. It is suggested that brivanib is effective in treating HCC.[2]
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| Enzyme Assay |
In Sf9 cells, recombinant proteins with tyrosine kinases are expressed as GST fusion proteins through the use of a baculovirus expression vector system. Every enzyme is kept in storage at -80 °C. Brivanib is mixed with 10% DMSO and dissolved in DMSO. Eight ng of the GST-VEGFR2 enzyme, 75 μg/mL of substrate, 1 μM ATP, and 0.04 μCi [γ-33P] make up the VEGFR2 kinase solution. -ATP in 50 μL buffer (20 mM Tris (pH 7.0), 25 μg/mL BSA, 1.5 mM MnCl2, 0.5 mM dithiothreitol). Ten nanograms of GST make up the Flk-1 kinase solution. -Flk-1 enzyme, 0.04 μCi [γ-33P], 1 μM ATP, and 75 μg/mL substrate. -ATP in a 50 μL buffer (20 mM Tris, pH 7.0, 25 μg/mL BSA, 4 mM MnCl2, 0.5 mM dithiothreitol). The reactions are stopped with cold trichloroacetic acid (TCA) at a final concentration of 15% after an hour of incubation at 27 °C. The liquid scintillation counter is used to quantify the TCA precipitates after they have been gathered onto unifilter plates.
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| Cell Assay |
At concentrations of 8 or 80 ng/mL, VEGF or FGF stimulates the cells. These cells are plated at a density of 2 × 103 in 96-well plates and left to grow for a full day. The cells are treated with different concentrations of Brivanib for an additional 48 hours. Next, add 0.5 μCi of [3H] thymidine and let it sit for a full day. A β-counter is then used to quantify the integrated tritium.
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| Animal Protocol |
H3396 xenografts in athymic mice
60 mg/kg (orally) or 10 mg/kg (intravenously) Administered via oral or i.v. |
| References |
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| Additional Infomation |
Brivanib is a secondary alcohol resulting from the hydrolysis of the carboxylic ester group of brivanib alaninate. It is a dual VEGFR-2/FGFR-1 kinase inhibitor whose alanine prodrug, brivanib alaninate is currently under development as an oral agent for the treatment of cancer. It has a role as an antineoplastic agent, an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor, an angiogenesis inhibitor, an apoptosis inducer, a fibroblast growth factor receptor antagonist and a drug metabolite. It is a pyrrolotriazine, a fluoroindole, a diether, an aromatic ether and a secondary alcohol.
Brivanib is under investigation for the treatment of HepatoCellular Carcinoma. Brivanib has been investigated for the treatment of Solid Tumors, Hepato Cellular Carcinoma (HCC), and Metastatic Colorectal Cancer (MCRC). Brivanib is a pyrrolotriazine-based compound and an inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) with potential antineoplastic activity. BMS-540215 specifically targets and binds strongly to human VEGFR-2, a tyrosine kinase receptor and pro-angiogenic growth factor expressed almost exclusively on vascular endothelial cells. Blockade of VEGFR-2 by this agent may lead to an inhibition of VEGF-stimulated endothelial cell migration and proliferation, thereby inhibiting tumor angiogenesis. |
| Molecular Formula |
C19H19FN4O3
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|---|---|
| Molecular Weight |
370.38
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| Exact Mass |
370.144
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| Elemental Analysis |
C, 61.61; H, 5.17; F, 5.13; N, 15.13; O, 12.96
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| CAS # |
649735-46-6
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| Related CAS # |
Brivanib (alaninate);649735-63-7
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| PubChem CID |
11234052
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| Appearance |
White to light brown solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.661
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| LogP |
2.48
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
27
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| Complexity |
515
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| Defined Atom Stereocenter Count |
1
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| SMILES |
FC1=C(C([H])=C([H])C2=C1C([H])=C(C([H])([H])[H])N2[H])OC1C2=C(C([H])([H])[H])C(=C([H])N2N=C([H])N=1)OC([H])([H])[C@@]([H])(C([H])([H])[H])O[H]
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| InChi Key |
WCWUXEGQKLTGDX-LLVKDONJSA-N
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| InChi Code |
InChI=1S/C19H19FN4O3/c1-10-6-13-14(23-10)4-5-15(17(13)20)27-19-18-12(3)16(26-8-11(2)25)7-24(18)22-9-21-19/h4-7,9,11,23,25H,8H2,1-3H3/t11-/m1/s1
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| Chemical Name |
(2R)-1-[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]oxypropan-2-ol
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| Synonyms |
Brivanib; BMS-540215; BMS 540215; BMS540215
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.62 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (5.62 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (5.62 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6999 mL | 13.4996 mL | 26.9993 mL | |
| 5 mM | 0.5400 mL | 2.6999 mL | 5.3999 mL | |
| 10 mM | 0.2700 mL | 1.3500 mL | 2.6999 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00207103 | Completed | Drug: Brivanib Drug: Brivanab |
Tumors Neoplasm Metastasis |
Bristol-Myers Squibb | September 2004 | Phase 1 |
| NCT00594984 | Completed | Drug: Brivanib Drug: Irinotecan |
Metastatic Colorectal Cancer (MCRC) |
Bristol-Myers Squibb | May 2008 | Phase 1 Phase 2 |
| NCT01540461 | Completed | Drug: Brivanib | Hepatocellular Carcinoma | Bristol-Myers Squibb | March 2012 | Phase 1 |
| NCT00437437 | Completed | Drug: Brivanib | Tumors | Bristol-Myers Squibb | May 2000 | Phase 1 |
| NCT01267253 | Completed | Drug: Brivanib Alaninate Other: Laboratory Biomarker Analysis |
Cervical Adenocarcinoma Persistent Disease |
Gynecologic Oncology Group | April 4, 2011 | Phase 2 |
Effects of brivanib on growth rate of patient-derived HCC xenograft lines 06-0606, 2-1318, and 26-1004. Clin Cancer Res. 2008 Oct 1;14(19):6146-53. |
Effects of brivanib on VEGFR-2 activity, cell proliferation, and apoptosis in HCC xenograft lines 06-0606 (A) and 26-1004 (B). Clin Cancer Res. 2008 Oct 1;14(19):6146-53. |
Effects of brivanibon (A and C) VEGF-induced, bFGF-induced, and (B) IGF-I–induced phosphorylation of VEGFR-2, FGFR, Akt, and ERK1/2 in SK-HEP1 (A and B) and HepG2 (C) cells. Clin Cancer Res. 2008 Oct 1;14(19):6146-53. |
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