Home Protein Tyrosine Kinase VEGFR inhibitor - FGFR inhibitor Brivanib Alaninate (BMS-582664) For research use only.

Brivanib Alaninate (BMS-582664)

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

Brivanib Alaninate (BMS-582664) Chemical Structure

Brivanib Alaninate (BMS-582664) Chemical Structure

CAS No. 649735-63-7

Purity & Quality Control

Brivanib Alaninate (BMS-582664) Related Products

Signaling Pathway

VEGFR Signaling Pathways

VEGFR Signaling Pathway

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
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]
Kinase Assay 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 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.
Experimental Result Images Methods Biomarkers Images PMID
Western blot VEGFR2 / p-VEGFR2 / ER / p-ER / β-Actin 20303261
Growth inhibition assay MCF-7 E2 tumors 20303261
IHC H&E staining in necrotic tissue 20303261
In Vivo
In vivo BMS-582664 (50 mg/kg) results in AUC of 136 μM×hr and Cmax of 41 μM in mouse. BMS-582664 (60 mg/kg, orally) is rapidly absorbed with Tmax of 1 hour, a favorable half-life (t1/2) 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]
Animal Research Animal Models H3396 xenografts athymic mice
Dosages 90 mg/kg
Administration Orally
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT00390936 Completed
Solid Tumors
Bristol-Myers Squibb
 October 2007 Phase 1
NCT00435669 Completed
Tumors
Bristol-Myers Squibb
 September 2007 Phase 1
NCT00437424 Completed
Carcinoma Hepatocellular
Bristol-Myers Squibb
 July 2007 Phase 1
NCT00437437 Completed
Tumors
Bristol-Myers Squibb
 May 2000 Phase 1

Chemical Information & Solubility

Molecular Weight 441.46 Formula

C22H24FN5O4
CAS No. 649735-63-7 SDF Download Brivanib Alaninate (BMS-582664) SDF
Smiles CC1=CC2=C(N1)C=CC(=C2F)OC3=NC=NN4C3=C(C(=C4)OCC(C)OC(=O)C(C)N)C
Storage (From the date of receipt)

In vitro
Batch:

DMSO : 88 mg/mL ( (199.33 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : 88 mg/mL

Water : Insoluble


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