Abstract |
Angiogenesis depends on vascular endothelial growth factor ( VEGF) for initiation and platelet-derived growth factor (PDGF) for maintenance of blood vessels. We have designed a targeted library of compounds from which we identified a novel molecule, GFB-204, that binds PDGF and VEGF, blocks binding of PDGF and VEGF to their receptors (200-500 nM) and subsequently inhibits PDGFR and Flk-1 tyrosine phosphorylation and stimulation of the protein kinases Erk1, Erk2 and Akt and the signal transducer and activator of transcription STAT3. GFB-204 is selective for PDGF and VEGF and does not inhibit EGF, IGF-1 and FGF stimulation of Erk1/2, Akt and STAT3. GFB-204 inhibits endothelial cell migration and capillary network formation in vitro. Finally, treatment of mice with GFB-204 suppresses human tumor growth and angiogenesis. Thus, inhibition of VEGF and PDGF receptor binding with a synthetic molecule results in potent inhibition of angiogenesis and tumorigenesis.
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Authors | Jiazhi Sun, De-An Wang, Rishi K Jain, Adam Carie, Steve Paquette, Eileen Ennis, Michelle A Blaskovich, Laura Baldini, Domenico Coppola, Andrew D Hamilton, Saïd M Sebti |
Journal | Oncogene
(Oncogene)
Vol. 24
Issue 29
Pg. 4701-9
(Jul 07 2005)
ISSN: 0950-9232 [Print] England |
PMID | 15897913
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- GFB-204
- Platelet-Derived Growth Factor
- Vascular Endothelial Growth Factor A
- Calixarenes
- Receptors, Platelet-Derived Growth Factor
- Receptors, Vascular Endothelial Growth Factor
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Topics |
- Animals
- Calixarenes
(pharmacology)
- Cell Movement
- Cell Transformation, Neoplastic
- Humans
- Mice
- Mice, Nude
- Neoplasms, Experimental
- Neovascularization, Pathologic
- Platelet-Derived Growth Factor
(physiology)
- Receptors, Platelet-Derived Growth Factor
(antagonists & inhibitors, physiology)
- Receptors, Vascular Endothelial Growth Factor
(antagonists & inhibitors, physiology)
- Transplantation, Heterologous
- Vascular Endothelial Growth Factor A
(physiology)
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