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Inhibiting angiogenesis and tumorigenesis by a synthetic molecule that blocks binding of both VEGF and PDGF to their receptors.

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.
AuthorsJiazhi 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
JournalOncogene (Oncogene) Vol. 24 Issue 29 Pg. 4701-9 (Jul 07 2005) ISSN: 0950-9232 [Print] England
PMID15897913 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • GFB-204
  • Platelet-Derived Growth Factor
  • Vascular Endothelial Growth Factor A
  • Calixarenes
  • Receptors, Platelet-Derived Growth Factor
  • Receptors, Vascular Endothelial Growth Factor
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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