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.
Sun
Jiazhi
J
Drug Discovery Program, H Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, MRC-DRDIS, Tampa, FL 33612, USA.
Wang
De-An
DA
Jain
Rishi K
RK
Carie
Adam
A
Paquette
Steve
S
Ennis
Eileen
E
Blaskovich
Michelle A
MA
Baldini
Laura
L
Coppola
Domenico
D
Hamilton
Andrew D
AD
Sebti
Saïd M
SM
D000818:Animals; D047250:Calixarenes / Q000494:pharmacology*; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
C502468:GFB-204; D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; D047250:Calixarenes; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor