Blocking angiogenesis and tumorigenesis with GFA-116, a synthetic molecule that inhibits binding of vascular endothelial growth factor to its receptor.
A small synthetic library of cyclohexapeptidomimetic calixarenes was prepared to identify disrupters of vascular endothelial growth factor (VEGF) binding to its receptor that inhibits angiogenesis. From this library, we discovered GFA-116, which potently inhibits (125)I-VEGF binding to Flk-1 in Flk-1-overexpressing NIH 3T3 cells and human prostate tumor cells with an IC(50) of 750 nM. This inhibition is highly selective for VEGF in that (125)I- platelet-derived growth factor binding to its receptor is not affected. GFA-116 inhibits VEGF-stimulated Flk-1 tyrosine phosphorylation and subsequent activation of Erk1/2 mitogen-activated protein kinases. Furthermore, epidermal growth factor, platelet-derived growth factor, and fibroblast growth factor-dependent stimulation of Erk1/2 phosphorylation are not affected at concentrations as high as 10 microM. In vitro, GFA-116 inhibits angiogenesis as measured by inhibition of migration and formation of capillary-like structures by human endothelial cells as well as suppression of microvessel outgrowth in rat aortic rings and rat cornea angiogenesis. In vivo, GFA-116 (50 mpk/day) inhibits tumor growth and angiogenesis as measured by CD31 staining of A-549 human lung tumors in nude mice. Furthermore, GFA-116 is also effective at inhibiting tumor growth and metastasis to the lung of B16-F10 melanoma cells injected into immunocompetent mice. Taken together, these results demonstrate that a synthetic molecule capable of disrupting the binding of VEGF to its receptor selectively inhibits VEGF-dependent signaling and suppresses angiogenesis and tumorigenesis.
Sun
Jiazhi
J
Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
Blaskovich
Michelle A
MA
Jain
Rishi K
RK
Delarue
Frederic
F
Paris
Daniel
D
Brem
Steven
S
Wotoczek-Obadia
Marguerite
M
Lin
Qing
Q
Coppola
Domenico
D
Choi
Kihang
K
Mullan
Michael
M
Hamilton
Andrew D
AD
Sebti
Saïd M
SM
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001921:Brain / Q000098:blood supply; D045744:Cell Line, Tumor; D003315:Cornea / Q000098:blood supply; D004730:Endothelium, Vascular / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D041681:NIH 3T3 Cells; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D001565:Benzoates; C488093:GFA 116; D010456:Peptides, Cyclic; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases