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|
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.
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