Brivanib (BMS-540215)

Catalog No.S1084

Brivanib is an ATP-competitive inhibitor against VEGFR2 with IC50 of 25 nM, moderate potency against VEGFR-1 and FGFR-1, but >240-fold against PDGFR-β. Phase 3.

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Brivanib (BMS-540215) Chemical Structure

Brivanib (BMS-540215) Chemical Structure
Molecular Weight: 370.38

Validation & Quality Control

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Quality Control & MSDS

Related Compound Libraries

Brivanib (BMS-540215) is available in the following compound libraries:

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Product Description

Biological Activity

Description Brivanib is an ATP-competitive inhibitor against VEGFR2 with IC50 of 25 nM, moderate potency against VEGFR-1 and FGFR-1, but >240-fold against PDGFR-β. Phase 3.
Targets VEGFR2 [1] Flk1 [1] FGFR1 [1] VEGFR1 [1]

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IC50 25 nM 89 nM 148 nM 380 nM
In vitro Brivanib also inhibits VEGFR1 and FGFR-1 with IC50 of 0.38 μM and 0.148 μM. Brivanib is not sensitive to PDGFRβ, EGFR, LCK, PKCα or JAK-3 with IC50 all above 1900 nM. Brivanib could inhibit the proliferation of VEGF-stimulated HUVECs with IC50 of 40 nM, compared to 276 nM in FGF-stimulated HUVECs. On the other hand, Brivanib exhibits low activity to tumor cell lines. [1]
In vivo Brivanib displays antitumor activities in H3396 xenograft in athymic mice. At a dose of 60 and 90 mg/kg (p.o.), Brivanib completely inhibits the tumor growth, with TGI of 85% and 97%, respectively. [1] Moreover, Brivanib significantly suppresses tumor growth in Hepatocellular carcinoma (HCC) xenografts, which due to the decrease in phosphorylation of VEGFR2. The results show that the tumor weights in 06-0606 xenograft mice are 55% and 13%, compared with the controls at a dose of 50 mg/kg and 100 mg/kg. Brivanib is suggested to be efficient in treatment of HCC. [2]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

In Vitro Kinase Assays Recombinant proteins containing tyrosine kinases are expressed as GST fusion proteins using baculovirus expression vector system in Sf9 cells. All enzymes are stored at -80 °C. Brivanib is dissolved in DMSO and diluted by water/10% DMSO. The VEGFR2 kinase solution is composed by 8 ng GST-VEGFR2 enzyme, 75 μg/mL substrate, 1 μM ATP, and 0.04 μCi [γ-33P]-ATP in 50 μL buffer: 20 mM Tris (pH 7.0), 25 μg/mL BSA, 1.5 mM MnCl2, 0.5 mM dithiothreitol). Flk-1 kinase solution is composed by 10 ng GST-Flk-1 enzyme, 75 μg/mL substrate, 1 μM ATP, and 0.04 μCi [γ-33P]-ATP in 50 μL buffer: 20 mM Tris, pH 7.0, 25 μg/mL BSA, 4 mM MnCl2, 0.5 mM dithiothreitol). The reactions are incubated for 1 hour at 27 °C and terminated with cold trichloroacetic acid (TCA) to a final concentration of 15%. These TCA precipitates are collected onto unifilter plates and quantitated by liquid scintillation counter.

Cell Assay: [1]

Cell lines VEGF or FGF stimulated HUVECs
Concentrations ~ 10 μM
Incubation Time 48 hours
Method The cells are stimulated by VEGF or FGF at a concentration of 8 or 80 ng/mL. These cells are seeded in 96 well plates at a density of 2 × 103 and incubated for 24 hours. Brivanib at various dilutions are added to the cells for another 48 hours. Then 0.5 μCi of [3H] thymidine is added for 24 hours. After that the incorporated tritium is quantified using a β-counter.

Animal Study: [1]

Animal Models H3396 xenografts in athymic mice
Formulation Dissolved in PEG400: Tween80 (75:25) (orally) or PEG400: water (3:2) (intravenously)
Dosages 60 mg/kg (orally) or 10 mg/kg (intravenously)
Administration Administered via oral or i.v.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Bhide RS, et al., J Med Chem, 2006, 49 (7), 2143-2146.

[2] Huynh H, et al. Clin Cancer Res, 2008, 14(19), 6146-6153.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-05-07)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01540461 Completed Hepatocellular Carcinoma Bristol-Myers Squibb March 2012 Phase 1
NCT01367275 Terminated Colorectal Cancer|Colorectal Adenocarcinoma M.D. Anderson Cancer Center|Bristol-Myers Squibb August 2011 Phase 2
NCT01267253 Suspended Cervical Cancer 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 Tre  ...more 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
NCT01108705 Terminated Carcinoma, Hepatocellular Bristol-Myers Squibb May 2010 Phase 3

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Chemical Information

Download Brivanib (BMS-540215) SDF
Molecular Weight (MW) 370.38
Formula

C19H19FN4O3

CAS No. 649735-46-6
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 74 mg/mL (199.79 mM)
Ethanol 3 mg/mL (8.09 mM)
Water <1 mg/mL (<1 mM)
* <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.
Chemical Name (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[1,2-f][1,2,4]triazin-6-yloxy)propan-2-ol

Customer Product Validation (1)


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Rating
Source Dr. Yong-Weon Yi from Georgetown University Medical Center.. Brivanib (BMS-540215) purchased from Selleck
Method MTT assays
Cell Lines MDA-MB-231 cells
Concentrations 0.01-10 μM
Incubation Time 72 h
Results BMS-540215 treatments reduced MDA-MB-231 cells growth.

Tech Support

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