Brivanib Alaninate (BMS-582664)

Name: Brivanib Alaninate (BMS-582664)
Brand: Selleck Chemicals
SKU: S1138
Rating: 5 (2 reviews)

For research use only.

Catalog No.S1138

2 publications

Brivanib Alaninate (BMS-582664) Chemical Structure

CAS No. 649735-63-7

Brivanib alaninate (BMS-582664) is the prodrug of BMS-540215, an ATP-competitive inhibitor against VEGFR2 with IC50 of 25 nM.

Selleck's Brivanib Alaninate (BMS-582664) has been cited by 2 publications

Int J Oncol, 2014, 44(3):959-69

PubMed: 24366069 ( click the link to review the publication )

Assay Drug Dev Technol, 2014, 12(9-10):514-26

PubMed: 25506801 ( click the link to review the publication )

1 Customer Review

Brivanib Alaninate (BMS-582664) purchased from Selleck.

Purity & Quality Control

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Biological Activity

Description

Brivanib alaninate (BMS-582664) is the prodrug of BMS-540215, an ATP-competitive inhibitor against VEGFR2 with IC50 of 25 nM.

Features

Alanine prodrug of BMS-540215.

Targets

VEGFR2 ^[1]	Flk1 ^[1]	FGFR1 ^[1]	VEGFR1 ^[1]
25 nM	89 nM	148 nM	380 nM

In vitro

BMS-582664 inhibits VEGF-stimulated and FGF-stimulated proliferating of HUVECs with IC50 of 40 nM and 276 nM. ^[1] BMS-582664 (2 μM) significantly inhibits VEGFR2, FGFR1, ERK1/2 and Akt phosphorylation in VEGF- and bFGF-stimulated SK-HEP1 cells and HepG-2 cells, while BMS-582664 alone has little effect on levels of phosphorylated ERK1/2, Akt, VEGFR2, and FGFR1 in nonstimulated cells. ^[2] BMS-582664 inhibits CYP2C19, CYP3A4(BFC) and CYP3A4 (BzRes) with IC50 of 2.4 μM, 0.51 μM and 1.6 μM, respectively. BMS-582664 exhibits high solid state stability (only 0.3% degradation at 50℃ with desiccant over a period of 12 weeks) and acceptable solution state stability up to pH 6.5. ^[3]

In vivo

BMS-582664 (50 mg/kg) results in AUC of 136 μM×hr and C_max of 41 μM in mouse. BMS-582664 (60 mg/kg, orally) is rapidly absorbed with T_max of 1 hour, a favorable half-life (t_1/2) of 2.7 hours and mean residence time (MRT) of 3.6 hours in mouse. BMS-582664 (25 mg/kg) results in AUC of 13.4 μM×hr and Cmax of 6.4 μM in rat. BMS-582664 dose-dependently inhibits the growth of established tumors with tumor growth inhibition of 85% and 97% at dose of 60 mg/kg and 90 mg/kg in H3396 xenografts athymic mice. ^[1] BMS-582664 inhibits the growth rate of tumors in mice with patient-derived xenograft line 06-0606 by 55% and 13% at dose of 50 mg/kg and 100 mg/kg. BMS-582664 (60 mg/kg, orally) significantly reduces tumor weight at sacrifice, increases apoptosis, reduces microvessel density, inhibits of cell proliferation, and down-regulates cell cycle regulators in mice with patient-derived xenograft line 06-0606. ^[2] BMS-582664 dose-dependently inhibits the growth of established tumors with tumor growth inhibition of 85% and 97% at dose of 80 mg/kg and 107 mg/kg in a L2987 nonsmall cell lung tumor xenografts assay in athymic mice. ^[3] BMS-582664 (100 mg/kg) significantly modulates tyrosine kinase receptor 1 (Tie-1), collagen type IV alpha1 (Col4a1), complement component 1, q subcomponent receptor 1 (C1qr1), angiotensin receptor-like 1 (Agtrl1), and vascular endothelial-cadherin (Cdh5) in L2987 nonsmall cell lung tumor xenografts assay in athymic mice. BMS-582664 (100 mg/kg) inhibits the new growth of endothelial cells in two xenografts mouse models, L2987 and HCT116. ^[4]

Protocol

Kinase Assay:^[1]	- Collapse Kinase inhibition assays: For the VEGFR2, Flk1 and FGFR1 kinase assays, BMS-582664 is dissolved in DMSO and diluted with water/10% DMSO to a final DMSO concentration of 2%. The kinase reactions consists of 8 ng of enzymes with GST tag, 75 μg/mL substrate, 1 μM ATP, and 0.04 μCi [γ-³³P]ATP in 50 μL total reaction volume (kinase buffer: 20 mM Tris, pH 7.0, 25 μg/mL BSA, 1.5 mM MnCl₂, 0.5 mM dithiothreitol). In all cases, the reactions are incubated for 60 min at 27℃ and terminated with the addition of cold trichloroacetic acid (TCA) to a final concentration of 15%. The percent inhibition from the kinase assays is determined by nonlinear regression analyses, and data are reported as the inhibitory concentration required to achieve 50% inhibition relative to control reactions (IC50).
Cell Research:^[1]	- Collapse Cell lines: HUVECs cell lines Concentrations: 276 nM Incubation Time: 72 hours Method: Cells are grown in 100 μL of minimal growth medium and 1.0% heat-inactivated fetal bovine serum in 96-well collagen IV coated plates at a density of 2 × 10³ per well in a 37 ℃/5% CO₂ environment. Twenty-four hours later, serum is adjusted to 10%, and BMS-582664 at various dilutions are added to each well in a final volume of minimal growth media that contains 10% serum. Forty-eight hours later, 0.5 μCi of [³H]thymidine is added in a volume of 20 μL of minimal media for 24 hours. Plates are washed once in PBS. Upon removal of PBS, Trypsin is added to cells which are subsequently harvested onto glass-fiber filters using an automated harvestor. Incorporated tritium is quantified using a β-counter. Dose−response curves are generated to determine the IC50 value, which is defined as the concentration of drug required to inhibit 50% of tritium incorporation when compared to untreated serum-stimulated cells. (Only for Reference)
Animal Research:^[1]	- Collapse Animal Models: H3396 xenografts athymic mice Dosages: 90 mg/kg Administration: Orally (Only for Reference)

References

[4] Ayers M, et al. Cancer Res, 2007, 67(14), 6899-6906.

- Collapse

Solubility (25°C)

In vitro	DMSO	88 mg/mL (199.33 mM)
	Ethanol	88 mg/mL (199.33 mM)
	Water	Insoluble
In vivo	Add solvents to the product individually and in order(Data is from Selleck tests instead of citations): 0.5% methylcellulose+0.2% Tween 80 For best results, use promptly after mixing.	10 mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information Download Brivanib Alaninate (BMS-582664) SDF

Molecular Weight	441.46
Formula	C₂₂H₂₄FN₅O₄
CAS No.	649735-63-7
Storage	3 years-20°C powder 2 years-80°C in solvent
Synonyms	N/A
Smiles	CC1=CC2=C(N1)C=CC(=C2F)OC3=NC=NN4C3=C(C(=C4)OCC(C)OC(=O)C(C)N)C

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Method for preparing DMSO master liquid: ： mg drug pre-dissolved in μL DMSO (Master liquid 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 master liquid, next addμL PEG300， mix and clarify, next addμL Tween 80，mix and clarify, next add μL ddH₂O，mix and clarify.

Note：1.Please make sure the liquid is clear before adding the next solvent.
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Clinical Trial Information (data from https://clinicaltrials.gov, updated on 2020-01-06)

NCT Number	Recruitment	interventions	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT00390936	Completed	Drug: Brivanib	Solid Tumors	Bristol-Myers Squibb	October 2007	Phase 1
NCT00435669	Completed	Drug: Brivanib	Tumors	Bristol-Myers Squibb	September 2007	Phase 1
NCT00437424	Completed	Drug: Brivanib	Carcinoma Hepatocellular	Bristol-Myers Squibb	July 2007	Phase 1
NCT00355238	Completed	Drug: brivanib (active)	Hepatocellular Carcinoma (HCC)	Bristol-Myers Squibb	December 2006	Phase 2
NCT00437437	Completed	Drug: Brivanib	Tumors	Bristol-Myers Squibb	May 2000	Phase 1

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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VEGFR Signaling Pathway Map

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Brivanib Alaninate (BMS-582664)