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

Jiazhi Sun, De An Wang, Rishi K. Jain, Adam Carie, Steve Paquette, Eileen Ennis, Michelle A. Blaskovich, Laura Baldini, Domenico Coppola, Andrew Hamilton, Saïd M. Sebti

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)4701-4709
Number of pages9
JournalOncogene
Volume24
Issue number29
DOIs
Publication statusPublished - Jul 7 2005

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Keywords

  • Angiogenesis inhibitors
  • Growth factor binders
  • PDGF
  • Tumorigenesis
  • VEGF

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Sun, J., Wang, D. A., Jain, R. K., Carie, A., Paquette, S., Ennis, E., ... Sebti, S. M. (2005). Inhibiting angiogenesis and tumorigenesis by a synthetic molecule that blocks binding of both VEGF and PDGF to their receptors. Oncogene, 24(29), 4701-4709. https://doi.org/10.1038/sj.onc.1208391