Uses
Brivanib is an ATP-competitive inhibitor against human VEGFR2 and FGFR with IC50 of 25 nM and 148 nM, respectively.
Definition
ChEBI: Brivanib is a secondary alcohol resulting from the hydrolysis of the carboxylic ester group of brivanib alaninate. It is a dual VEGFR-2/FGFR-1 kinase inhibitor whose alanine prodrug, brivanib alaninate is currently under development as an oral agent for the treatment of cancer. It has a role as an antineoplastic agent, an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor, an angiogenesis inhibitor, an apoptosis inducer, a fibroblast growth factor receptor antagonist and a drug metabolite. It is a pyrrolotriazine, a fluoroindole, a diether, an aromatic ether and a secondary alcohol.
Biological Activity
BMS-540215 is an ATP-competitive inhibitor of human VEGFR-2, with an IC50 of 25 nM and Ki of 26 nmol/l. BMS-540215 also showed good selectivity for FGFR-1 (IC50 of 48 nM), FGFR-2 (IC50 of 125 nM), and FGFR-3 (IC50 of 68 nM).
Enzyme inhibitor
This ATP-competitive VEGFR inhibitor (FW = 370.38 g/mol; CAS 649735-
46-6; Solubility: 74 mg/mL DMSO, <1 mg/mL H2O), also named (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 and Brivanib?, targets human Vascular Endothelial
Growth Factor-2 Receptor, or VEGFR-2 (IC = 25 nM; K = 26 nM), with
50i
VEGFR-1 (IC50 = 0.38 μM) and FGFR-1 (IC50 = 0.148 μM). Because
brivanib has a high oral dose (60 mg/kg) relative to its intravenous dose (10
mg/kg), its alanine ester is a more effective oral drug (See Brivanib Alanate)
. BMS-540215 is only weakly active against PDGFRβ, EGFR, LCK,
PKCα or JAK-3, all with IC50 values >1.9 μM. BMS-540215 selectively
inhibits VEGF- and FGF-stimulated endothelial cell (HUVEC) proliferation
in vitro, with respective IC50 values of 40 and 276 nM. Furthermore,
brivanib-induced growth inhibition was associated with a decrease in
phosphorylated VEGFR-2 at Tyr (1054/1059), increased apoptosis, reduced
microvessel density, inhibition of cell proliferation, and down-regulation of
cell cycle regulators. The levels of FGFR-1 and FGFR-2 expression in these
xenograft lines were positively correlated with its sensitivity to brivanib-
induced growth inhibition. It also shows broad-spectrum in vivo
antitumor activity over multiple dose levels and induces stasis in large
tumors, with potential for treating hepatocellular carcinoma (HCC).
References
[1] rajeev s. bhide, zhen-wei cai, yong-zheng zhang, ligang qian, donna wei, stephanie barbosa, louis j. lombardo, robert m. borzilleri, xiaoping zheng, laurence i. wu, joel c. barrish, soong-hoon kim, kenneth leavitt, arvind mathur, leslie leith, sam chao, barri wautlet, steven mortillo, robert jeyaseelan sr., daniel kukral, john t. hunt, amrita kamath, aberra fura, viral vyas, punit marathe, celia d’arienzo, george derbin, and joseph fargnoli. discovery and preclinical studies of (r)-1-(4-(4-fluoro-2-methyl-1h-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-ol (bms-540215), an in vivo active potent vegfr-2 inhibitor. journal of medicinal chemistry. 2006, 49 (7): 2143-2146.
[2] elizabeth allen, ian b. walters, and douglas hanahan. brivanib, a dual fgf/vegf inhibitor, is active both first and second line against mouse pancreatic neuroendocrine tumors developing adaptive/evasive resistance to vegf inhibition. clinical cancer research. 2011 (17): 5299-5310.
