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.
Original language | English (US) |
---|---|
Pages (from-to) | 4701-4709 |
Number of pages | 9 |
Journal | Oncogene |
Volume | 24 |
Issue number | 29 |
DOIs | |
State | Published - Jul 7 2005 |
Keywords
- Angiogenesis inhibitors
- Growth factor binders
- PDGF
- Tumorigenesis
- VEGF
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research