Brivanib Alaninate (BMS-582664)

Alias: BMS582664; BMS-582664; Brivanib Alaninate; BMS 582664

Cat No.:V0512 Purity: ≥98%

COA Product Data Instructions for use SDS

Brivanib alaninate (formerly BMS-582664) is the alaninate ester form and prodrug of Brivanib, which is an investigational and ATP-competitive inhibitor of VEGFR2 with potential anticancer activity.

Brivanib Alaninate (BMS-582664) Chemical Structure CAS No.: 649735-63-7
Product category: VEGFR

This product is for research use only, not for human use. We do not sell to patients.

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Other Forms of Brivanib Alaninate (BMS-582664):

Brivanib (BMS-540215)

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Top Publications Citing lnvivochem Products

Nature 2021, 597(7874):119-125.

Cell 2020,183:1202-1218.e25.

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Nature 597, 119–125 (2021)

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Cancer Cell 2021,39(4):529-547.e7.

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Immunity 2023,56(3):620-634.e11.

J Am Chem Soc 2022,144:21831-21836.

Cell 2020,183:1202-1218.e25.

Science Adv 2022:8,eabm9427.

Nature 2021,597(7874):119-125.

Cell 2020,183:1202-1218.e25.

PNAS Nexus 2022,1(3):pgac063.

ACS Nano 2023,17(10):9110-9125.

Biomaterial 2023 Sep16:302:122333.

Purity & Quality Control Documentation

Current batch：

Purity: ≥98%

COA

MSDS

Instructions

Product Description
Bioactivity & Protocols
Physicochemical Properties
Solubility Data
Calculators
Clinical Trial Information
Biological Data

Product Description

Brivanib alaninate (formerly BMS-582664) is the alaninate ester form and prodrug of Brivanib, which is an investigational and ATP-competitive inhibitor of VEGFR2 with potential anticancer activity. It exhibits >240-fold selectivity over PDGFR-β but moderate potency against VEGFR-1 and FGFR-1. Its IC50 for VEGFR2 inhibition is 25 nM. Brivanib alaninate is hydrolyzed to become Brivanib. Both in vitro and in vivo antitumor efficaciousness are demonstrated by its strong anti-proliferative activity.

Biological Activity I Assay Protocols (From Reference)

Targets

VEGFR2 (IC50 = 25 nM); Flk1 (IC50 = 89 nM); FGFR1 (IC50 = 148 nM); VEGFR1 (IC50 = 380 nM)

ln Vitro

Brivanib has an IC50 of 0.38 μM for VEGFR1 and 0.148 μM for FGFR-1. With an IC50 above 1900 nM, brivanib is insensitive to PDGFRβ, EGFR, LCK, PKCα, and JAK-3. Brivanib had an IC50 of 40 nM for VEGF-stimulated HUVECs and 276 nM for FGF-stimulated HUVECs in order to inhibit their proliferation. Brivanib, on the other hand, shows little activity against tumor cell lines[1]. Higher brivanib doses (≥30 µM) inhibit LX-2 cell proliferation, while brivanib doses ≤20 µM paradoxically enhance FGF-induced LX-2 cell proliferation. Brivanib may have an inhibitory effect on liver fibrosis through blocking PDGF-BB-induced stellate cell activation, rather than TGF-β 1-induced stellate cell activation[3].

ln Vivo

Brivanib exhibits antitumor properties in athymic mice using an H3396 xenograft. Brivanib fully inhibits tumor growth at doses of 60 and 90 mg/kg (p.o. ), with TGI of 85% and 97%, respectively[1]. Furthermore, brivanib dramatically inhibits the growth of tumors in xenografts of hepatocellular carcinoma (HCC), a phenomenon that is caused by a reduction 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]. In mice, BDL-induced liver fibrosis and stellate cell activation are attenuated by brivanib (50 mg/kg, p.o.). Brivanib exhibits varying effects in animals with bile duct ligation, but it inhibits the expression of growth factors and growth factor receptors in sham control animals[3].

Enzyme Assay

BMS-582664 is dissolved in DMSO and diluted with water/10% DMSO to a final DMSO concentration of 2% for the VEGFR2, Flk1, and FGFR1 kinase assays. Eight ng of GST-tagged enzymes, 75 μg/mL of substrate, 1 μM ATP, and 0.04 μCi [γ-³³P]ATP are included in the 50 μL total reaction volume of the kinase reactions (kinase buffer: 20 mM Tris, pH 7.0, 25 μg/mL BSA, 1.5 mM MnCl₂, 0.5 mM dithiothreitol). All reactions are brought to a final concentration of 15% by adding cold trichloroacetic acid (TCA) after they have been incubated for 60 minutes at 27°C. Nonlinear regression analyses are used to calculate the percent inhibition from the kinase assays. The data are presented as the inhibitory concentration needed to achieve 50% inhibition in comparison to control reactions (IC50).

Cell Assay

LX-2 cell viability is assessed using the Cell Counting Kit-8 (CCK-8). HSCs are cultivated in DMEM supplemented with 10% FBS for 24 hours using 96-well plates containing 2,000 cells per well. Subsequently, the cells are starved in serum-free media. Different doses of brivanib are added following a 24-hour fast. Add 5 ng/mL PDGF-BB after 2 hours. After a further 72 hours of incubation, the cells' viability is assessed. Every experiment is run through at least four times in three replicates[3].

Animal Protocol

Three intraperitoneal (i.p.) injections of 150 mL/kg TAA are administered three times a week to male mice aged 4-6 weeks. Brivanib (25 or 50 mg/kg) or a placebo is given orally for five days in a row, with weekends off, to commence TAA treatment. Four weeks following the start of the injections, the animals are killed[3].

References

[1]. Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan- 2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor. J Med Chem, 2006, 49 (7), 2143-2146.

[2]. Correction: Brivanib Attenuates Hepatic Fibrosis In Vivo and Stellate Cell Activation In Vitro by Inhibition of FGF, VEGF and PDGF Signaling. PLoS One. 2015 Nov 3;10(11):e0142355.

[3]. Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma. Clin Cancer Res. 2008 Oct 1;14(19):6146-53.

These protocols are for reference only. InvivoChem does not independently validate these methods.

Physicochemical Properties

Molecular Formula	C22H24FN5O4
Molecular Weight	441.46
Exact Mass	441.18
Elemental Analysis	C, 59.86; H, 5.48; F, 4.30; N, 15.86; O, 14.50
CAS #	649735-63-7
Related CAS #	Brivanib;649735-46-6
Appearance	Solid powder
SMILES	CC1=CC2=C(N1)C=CC(=C2F)OC3=NC=NN4C3=C(C(=C4)OC[C@@H](C)OC(=O)[C@H](C)N)C
InChi Key	LTEJRLHKIYCEOX-OCCSQVGLSA-N
InChi Code	InChI=1S/C22H24FN5O4/c1-11-7-15-16(27-11)5-6-17(19(15)23)32-21-20-13(3)18(8-28(20)26-10-25-21)30-9-12(2)31-22(29)14(4)24/h5-8,10,12,14,27H,9,24H2,1-4H3/t12-,14+/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-yl] (2S)-2-aminopropanoate
Synonyms	BMS582664; BMS-582664; Brivanib Alaninate; BMS 582664
HS Tariff Code	2934.99.9001
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)

Solubility Data

Solubility (In Vitro)

DMSO: ~88 mg/mL (~199.3 mM)

Water: <1 mg/mL

Ethanol: ~88 mg/mL (~199.3 mM)

Solubility (In Vivo)

Solubility in Formulation 1: 2.08 mg/mL (4.71 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 (4.71 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
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.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.71 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly.

Solubility in Formulation 4: 0.5% methylcellulose+0.2% Tween 80: 10mg/mL

(Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.2652 mL	11.3261 mL	22.6521 mL
	5 mM	0.4530 mL	2.2652 mL	4.5304 mL
	10 mM	0.2265 mL	1.1326 mL	2.2652 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.

Calculator

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An example of molarity calculation using the molarity calculator is shown below:
What is the mass of compound required to make a 10 mM stock solution in 5 ml of DMSO given that the molecular weight of the compound is 350.26 g/mol?

Enter 350.26 in the Molecular Weight (MW) box
Enter 10 in the Concentration box and choose the correct unit (mM)
Enter 5 in the Volume box and choose the correct unit (mL)
Click the “Calculate” button
The answer of 17.513 mg appears in the Mass box. In a similar way, you may calculate the volume and concentration.

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Dilution Calculator allows you to calculate how to dilute a stock solution of known concentrations. For example, you may Enter C1, C2 & V2 to calculate V1, as detailed below:

What volume of a given 10 mM stock solution is required to make 25 ml of a 25 μM solution?
Using the equation C1V1 = C2V2, where C1=10 mM, C2=25 μM, V2=25 ml and V1 is the unknown:

Enter 10 into the Concentration (Start) box and choose the correct unit (mM)
Enter 25 into the Concentration (End) box and select the correct unit (mM)
Enter 25 into the Volume (End) box and choose the correct unit (mL)
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The answer of 62.5 μL (0.1 ml) appears in the Volume (Start) box

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Molecular Weight Calculator allows you to calculate the molar mass and elemental composition of a compound, as detailed below:

Note: Chemical formula is case sensitive: C12H18N3O4 c12h18n3o4
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Definitions of molecular mass, molecular weight, molar mass and molar weight:

Molecular mass (or molecular weight) is the mass of one molecule of a substance and is expressed in the unified atomic mass units (u). (1 u is equal to 1/12 the mass of one atom of carbon-12)
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Reconstitution Calculator allows you to calculate the volume of solvent required to reconstitute your vial.

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The answer appears in the Volume (to add to vial) box

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)

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Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)

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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.

Note： (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.

Clinical Trial Information

NCT Number	Recruitment	interventions	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT01267253	Completed	Other: Laboratory Biomarker Analysis Drug: Brivanib Alaninate	Cervical Adenocarcinoma Persistent Disease	Gynecologic Oncology Group	April 4, 2011	Phase 2
NCT00437437	Completed	Tumors	Bristol-Myers Squibb	Astellas Pharma Inc	May 2000	Phase 1
NCT00888173	Completed	Other: Laboratory Biomarker Analysis Drug: Brivanib Alaninate	Endometrial Transitional Cell Carcinoma Endometrial Adenocarcinoma	Gynecologic Oncology Group	July 6, 2009	Phase 2
NCT00798252	Completed	Drug: Brivanib alaninate Drug: Paclitaxel	Advanced Cancer	Bristol-Myers Squibb	March 2009	Phase 1

Biological Data

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.

Brivanib Alaninate (BMS-582664)

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.