A novel low molecular weight antagonist of vascular endothelial growth factor receptor binding: VGA1155.
Vascular endothelial growth factor (VEGF) plays a pivotal role in the processes of angiogenesis, which is essential for the growth of solid tumors and their metastasis. Because VEGF is a critical factor in tumor survival, inhibiting VEGF would provide significant benefits in tumor therapy. To identify a compound that inhibits the binding of VEGF to its receptor, we used a high throughput screening method, finding that small molecular compounds inhibited VEGF binding. Among active compounds, 5-[N-methyl-N-(4-octadecyloxyphenyl)acetyl]amino-2-methylthiobenzoic acid (VGA1155) was selected for its potent inhibition of binding. VGA1155 inhibited [(125)I] VEGF binding to two cell lines, NIH3T3-fms-like tyrosine kinase-1 (VEGF receptor 1 transfected) cells and NIH3T3-kinase insert domain containing receptor/fetal liver kinase-1 (KDR/Flk-1; VEGF receptor 2 transfected), in a concentration-dependent manner. VGA1155 did not inhibit the binding of several other growth factors or cytokines to their receptors. Based on the results of surface plasmon resonance analysis using Biacore S51 system, it appears that this binding inhibitory property may be based on the association of VGA1155 with VEGF receptor 2 (KDR/Flk-1). Further, the interference in VEGF binding by VGA1155 in turn induces the inhibition of VEGF-induced KDR/Flk-1 autophosphorylation. VGA1155 also reduced intradermal VEGF-induced vascular permeability in guinea pigs. These findings indicate that VGA1155 inhibits not only VEGF binding to its receptors through association with KDR/Flk-1 but also VEGF function in vivo. These VGA1155 activities may provide a useful basis for the development of antiangiogenic and antitumor agents.
Ueda
Yasuji
Y
Taisho Pharmaceutical Co., Ltd., Saitama, Japan. y.ueda@po.rd.taish.co.jp
Yamagishi
Takehiro
T
Samata
Kazunori
K
Ikeya
Hisao
H
Hirayama
Noriko
N
Takashima
Hajime
H
Nakaike
Shiro
S
Tanaka
Makoto
M
Saiki
Ikuo
I
D000818:Animals; D001565:Benzoates / Q000737:chemistry* / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects; D005786:Gene Expression Regulation; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D008970:Molecular Weight; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D001565:Benzoates; C487956:VGA1155; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2