18 research outputs found
Structure-activity studies on a library of potent calix[4]arene-based PDGF antagonists that inhibit PDGF-stimulated PDGFR tyrosine phosphorylation.
Platelet-derived growth factor (PDGF) and its receptor PDGFR are required for tumor growth and angiogenesis, so disruption of the PDGF–PDGFR interaction should lead to starvation of tumors and reduction of tumor growth. Potent PDGF antagonists have been discovered through the synthesis of a series of calix[4]arene-based compounds that are designed to bind to the three-loop region of PDGF. The effect of lower-rim alkylation, linker and number of interacting head groups on the calix[4]arene scaffold on PDGF affinity and cellular activity has been investigated
Inhibiting angiogenesis and tumorigenesis by a synthetic molecule that blocks binding of both VEGF and PDGF to their receptors
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