Brivanib (BMS-540215)

 

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	FGFR
IC50	25 nM	148 nM [1]
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
Dosages	60 mg/kg (orally) or 10 mg/kg (intravenously)
Administration	Administered via oral or i.v.

1

References

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number	Recruitment	Conditions	Sponsor /Collaborators	Start Date	Phases
NCT01108705	Recruiting	Carcinoma, Hepatocellular	Bristol-Myers Squibb	2010-01	Phase 3
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	2010-11	Phase 2
NCT01267253	Suspended	Cervical Cancer	National Cancer Institute (NCI)|Gynecologic Oncology Group	2011-04	Phase 2
NCT01367275	Active, not recruiting	Colorectal Cancer|Colorectal Adenocarcinoma	M.D. Anderson Cancer Center|Bristol-Myers Squibb	2011-08	Phase 2
NCT01540461	Active, not recruiting	Hepatocellular Carcinoma	Bristol-Myers Squibb	2012-04	Phase 1

Chemical Information

Download Brivanib (BMS-540215) SDF

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

Preparing Stock Solutions

Stock Solution (1ml DMSO)	1mM	10mM	20mM	30mM
Mass(mg)	0.37038	3.7038	7.4076	11.1114

Customer Reviews (1)

Click to enlarge	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.