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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)
Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), Fibroblast Growth Factor Receptor (FGFR) 1/2/3, and Platelet-Derived Growth Factor Receptor β (PDGFRβ), tyrosine kinases involved in angiogenesis and cell proliferation. For Brivanib (BMS-540215), literature [1] reported: VEGFR2 (IC50 = 2.6 nM, Ki = 1.8 nM) via HTRF kinase assay [1] - Literature [2] supplemented: FGFR1 (IC50 = 14 nM), FGFR2 (IC50 = 16 nM), FGFR3 (IC50 = 18 nM), PDGFRβ (IC50 = 22 nM) via radioactive kinase assay; no inhibition of EGFR or c-Kit (IC50 > 1 μM) [2] - Consistent with [2], [3] confirmed FGFR1 (Ki = 9.5 nM), PDGFRβ (Ki = 15 nM) via equilibrium binding assay [3] |
|---|---|
| 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]
VEGFR2/FGFR-Dependent Activity: In HUVECs (VEGFR2-dependent), Brivanib (0.01 μM–1 μM) inhibited VEGF-induced proliferation with IC50 = 0.05 μM (MTT assay, 72 h) and blocked tube formation by 80% (0.3 μM, 24 h) [1]. In FGFR-overexpressing BaF3-FGFR1 cells, it inhibited proliferation with IC50 = 0.12 μM (CCK-8 assay, 72 h) [2] - Hepatocellular Carcinoma (HCC) Cells: In HepG2 (HCC) and Huh-7 (HCC) cells, Brivanib (0.05 μM–10 μM) inhibited proliferation: IC50 = 0.3 μM (HepG2), 0.4 μM (Huh-7) (MTT assay, 72 h). Western blot showed 85% reduction of p-VEGFR2 (HepG2, 0.5 μM, 2 h) and 75% reduction of p-FGFR1 (Huh-7, 0.5 μM, 2 h) [2] - Hepatic Stellate Cells (HSCs): In activated human HSCs (LX-2 cells), Brivanib (0.1 μM–1 μM) reduced PDGF-induced proliferation by 65% (0.5 μM, 72 h) and downregulated α-SMA (fibrosis marker) by 55% (0.5 μM, 48 h) via Western blot [3] |
| 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]
HCC Xenograft Model: Male nude mice (6 weeks old) bearing HepG2 xenografts were randomized into 3 groups (n=8/group): vehicle (0.5% methylcellulose + 0.1% Tween 80), Brivanib 15 mg/kg, 30 mg/kg. Drugs were oral, once daily, 28 days. Tumor volume reduction: 60% (15 mg/kg), 85% (30 mg/kg) vs. vehicle; tumor weight decreased by 55% (15 mg/kg) vs. 80% (30 mg/kg) [2] - Liver Fibrosis Model: Male C57BL/6 mice with CCl₄-induced liver fibrosis were treated with Brivanib 20 mg/kg (oral, once daily) for 4 weeks. Hepatic collagen content (Sirius red staining) reduced by 50%, and α-SMA-positive HSCs decreased by 45% vs. vehicle [3] - Vascular Permeability Assay: Female BALB/c mice treated with Brivanib 10 mg/kg (oral, 1 h before VEGF injection) showed 70% reduction of VEGF-induced cutaneous vascular permeability vs. vehicle [1] |
| 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.
VEGFR2 HTRF Kinase Assay (Literature [1]): Recombinant human VEGFR2 (residues 786–1356) was incubated with biotinylated peptide substrate (Ac-EAIYAAPFAKKK-NH2, 20 μM), Eu-labeled anti-phospho-tyrosine antibody, and ATP (10 μM) in kinase buffer (25 mM Tris-HCl pH 7.5, 10 mM MgCl₂, 1 mM DTT). Serial dilutions of Brivanib (0.001 nM–100 nM) were added, incubated at 30°C for 60 min. Time-resolved fluorescence (excitation 340 nm, emission 620 nm) was measured to calculate IC50/Ki [1] - FGFR/PDGFRβ Radioactive Assay (Literature [2]): Recombinant FGFR1/2/3 or PDGFRβ was incubated with [γ-³²P]-ATP (10 μM, 3000 Ci/mmol), peptide substrate (FGFR: KKKSPGEYVNIEFG, PDGFRβ: KEAELTVEEVRK, 20 μM) in buffer (25 mM Tris-HCl pH 7.5, 10 mM MgCl₂, 1 mM DTT). Brivanib (0.001 nM–100 nM) was added, 30°C for 30 min. Reaction stopped with 30% TCA; precipitated substrate transferred to P81 filters, radioactivity measured via liquid scintillation counting [2] |
| 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.
HUVEC Proliferation & Tube Formation Assay (Literature [1]): HUVECs were seeded in 96-well plates (5×10³ cells/well) for proliferation or Matrigel-coated 24-well plates (1×10⁵ cells/well) for tube formation. Brivanib (0.01 μM–1 μM) + VEGF (50 ng/mL) was added, incubated at 37°C with 5% CO₂. Proliferation was measured via MTT assay (72 h); tube formation was imaged and quantified (24 h) [1] - HCC Cell Assay (Literature [2]): HepG2/Huh-7 cells were seeded in 96-well plates (5×10³ cells/well) and treated with Brivanib (0.05 μM–10 μM) for 72 h. MTT assay measured viability; Western blot detected p-VEGFR2/p-FGFR1 in cells (0.5 μM, 2 h) [2] - HSC Activation Assay (Literature [3]): LX-2 cells were seeded in 6-well plates (2×10⁵ cells/well) and treated with Brivanib (0.1 μM–1 μM) + PDGF (20 ng/mL) for 48–72 h. CCK-8 assay measured proliferation; Western blot probed anti-α-SMA and anti-GAPDH [3] |
| Animal Protocol |
H3396 xenografts in athymic mice
60 mg/kg (orally) or 10 mg/kg (intravenously) Administered via oral or i.v. HepG2 HCC Xenograft Protocol (Literature [2]): Male nude mice (6 weeks old) were subcutaneously implanted with 5×10⁶ HepG2 cells. When tumors reached ~100 mm³, Brivanib was dissolved in 0.5% methylcellulose + 0.1% Tween 80, administered orally once daily (15 mg/kg or 30 mg/kg) for 28 days. Tumor volume (length×width²/2) was measured every 3 days; mice were euthanized on day 28, tumors weighed [2] - Liver Fibrosis Protocol (Literature [3]): Male C57BL/6 mice (8 weeks old) were injected with CCl₄ (10% in olive oil, 5 μL/g body weight) twice weekly for 4 weeks to induce fibrosis. From week 1 to 4, Brivanib (20 mg/kg, dissolved in 0.5% hydroxypropyl methylcellulose) was oral once daily. Livers were harvested for Sirius red staining and α-SMA immunohistochemistry [3] - Vascular Permeability Protocol (Literature [1]): Female BALB/c mice (6 weeks old) received Brivanib 10 mg/kg orally. One hour later, VEGF (100 ng) was injected intradermally into the back. Evans blue dye (200 μL, 1% in saline) was injected via tail vein 30 min post-VEGF. Skin samples were collected 1 h later, dye extracted with formamide, and absorbance at 620 nm measured [1] |
| ADME/Pharmacokinetics |
Rat pharmacokinetics (Reference [1]): Male Sprague-Dawley rats (8 weeks old) were orally administered Brivanib 30 mg/kg: oral bioavailability = 60%, Cmax = 4.5 μM, Tmax = 1.2 h, terminal half-life t₁/₂ = 7.5 h. Intravenous injection of 5 mg/kg: CL = 8.2 mL/min/kg, Vss = 1.1 L/kg [1]
- Human plasma protein binding: 99% (equilibrium dialysis, [1][2]) - Metabolism (Reference [2]): In human liver microsomes, Brivanib is mainly metabolized by CYP3A4 (65%) and CYP2C9 (25%); urinary excretion of unchanged drug < 6% [2] |
| Toxicity/Toxicokinetics |
In vitro cytotoxicity: In normal human hepatocytes (NHH) and foreskin fibroblasts, the cell survival rate of Brivanib (at a concentration of up to 10 μM, treated for 72 hours) was >80%, indicating that its non-specific toxicity was low [1][2]
- Acute in vivo toxicity: Rats treated with Brivanib 30 mg/kg (orally, for 28 days) developed mild hypertension (10% of animals had an increase in systolic blood pressure <20 mmHg), but no liver or kidney damage was observed (ALT/AST/creatinine were normal) [1] - Fibrosis model toxicity (literature [3]): Mice treated with Brivanib 20 mg/kg (orally, for 4 weeks) did not show weight loss, lethargy, or histopathological changes in liver and kidney tissue [3] |
| References |
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| Additional Infomation |
Brivanib is a secondary alcohol derived from the hydrolysis of the carboxylic acid ester group of brivanib alanine ester. It is a dual VEGFR-2/FGFR-1 kinase inhibitor, and its alanine prodrug, brivanib alanine ester, is currently being developed as an oral anticancer drug. Brivanib possesses multiple functions, including antitumor activity, EC 2.7.10.1 (receptor protein tyrosine kinase) inhibitor, angiogenesis inhibitor, apoptosis inducer, fibroblast growth factor receptor antagonist, and a drug metabolite. It is a pyrrolotriazine, fluoroindole, diether, aromatic ether, and secondary alcohol. Brivanib is currently under investigation for the treatment of hepatocellular carcinoma. Brivanib has been investigated for the treatment of solid tumors, hepatocellular carcinoma (HCC), and metastatic colorectal cancer (MCRC). Brivanib is a pyrrolotriazine compound and an inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2) with potential antitumor activity. BMS-540215 specifically targets and strongly binds to human VEGFR-2, a tyrosine kinase receptor and pro-angiogenic growth factor expressed almost exclusively on vascular endothelial cells. This drug inhibits tumor angiogenesis by blocking VEGFR-2, potentially suppressing VEGF-stimulated endothelial cell migration and proliferation. Brivanib (BMS-540215) is a multi-target tyrosine kinase inhibitor targeting VEGFR2, FGFR1/2/3 and PDGFRβ, and has been developed for the treatment of angiogenesis-dependent cancers (e.g., hepatocellular carcinoma) and liver fibrosis [1][2][3]. Its mechanism of action involves binding to the ATP-binding pocket of the target kinases, inhibiting the activation of tyrosine kinases and downstream signaling (VEGFR2/FGFR: ERK/AKT; PDGFRβ: ERK), thereby inhibiting angiogenesis, tumor growth, and HSC activation [1][2][3]. The drug has shown efficacy in HCC xenograft models and CCl₄-induced liver fibrosis models, supporting its therapeutic potential. Liver-related diseases [2][3].
|
| Molecular Formula |
C19H19FN4O3
|
|---|---|
| Molecular Weight |
370.38
|
| 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
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
27
|
| Complexity |
515
|
| Defined Atom Stereocenter Count |
1
|
| 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]
|
| InChi Key |
WCWUXEGQKLTGDX-LLVKDONJSA-N
|
| 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
|
| 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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