Brivanib Alaninate (BMS-582664)
Molecular Weight(MW): 441.46
Brivanib alaninate (BMS-582664) is the prodrug of BMS-540215, an ATP-competitive inhibitor against VEGFR2 with IC50 of 25 nM.
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|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.|
BMS-582664 inhibits VEGF-stimulated and FGF-stimulated proliferating of HUVECs with IC50 of 40 nM and 276 nM.  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.  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. 
|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.  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.  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.  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. |
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).
|In vitro||DMSO||88 mg/mL (199.33 mM)|
|Ethanol||88 mg/mL (199.33 mM)|
|In vivo||0.5% methylcellulose+0.2% Tween 80||10 mg/mL|
* 1 mg/ml means slightly soluble or insoluble.
* 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.
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Clinical Trial Information
|NCT Number||Recruitment||Conditions||Sponsor/Collaborators||Start Date||Phases|
|NCT01267253||Completed||Cervical Adenocarcinoma|Cervical Adenosquamous Carcinoma|Cervical Squamous Cell Carcinoma, Not Otherwise Specified|Persistent Disease|Recurrent Cervical Carcinoma||Gynecologic Oncology Group|National Cancer Institute (NCI)||April 2011||Phase 2|
|NCT01253668||Completed||Male and Female Subjects 18 Years of Age and Older With Metastatic Renal Cell Carcinoma. Eligible Patients Must Have Undergone and Failed Prior Treatment.||Abramson Cancer Center of the University of Pennsylvania||November 2010||Phase 2|
|NCT00888173||Active, not recruiting||Endometrial Adenocarcinoma|Endometrial Clear Cell Adenocarcinoma|Endometrial Mixed Adenocarcinoma|Endometrial Mucinous Adenocarcinoma|Endometrial Serous Adenocarcinoma|Endometrial Squamous Cell Carcinoma|Endometrial Transitional Cell Carcinoma|Endometrial Undifferentiated Carcinoma|Recurrent Uterine Corpus Carcinoma||Gynecologic Oncology Group|National Cancer Institute (NCI)||July 2009||Phase 2|
|NCT00798252||Completed||Advanced Cancer||Bristol-Myers Squibb||March 2009||Phase 1|
|NCT00640471||Completed||Colorectal Cancer||NCIC Clinical Trials Group|Canadian Cancer Trials Group||May 2008||Phase 3|
|NCT00300027||Terminated||Gastrointestinal Neoplasms||Bristol-Myers Squibb||April 2006||Phase 1|
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