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

Oncogene volume 24, pages 4701–4709 (2005)Cite this article

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.

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Acknowledgements

This work was supported by National Institutes of Health grants CA 78038 (SMS and ADH) and GM35208 (ADH).

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Author notes

  1. Jiazhi Sun and De-an Wang: These authors contributed equally to this work

Authors and Affiliations

  1. Drug Discovery Program, H Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, MRC-DRDIS, Tampa, FL, 33612, USA

    Jiazhi Sun, De-an Wang, Adam Carie, Steve Paquette, Michelle A Blaskovich & Saïd M Sebti

  2. Departments of Interdisciplinary Oncology and Biochemistry & Molecular Biology, University of South Florida, Tampa, FL, 33412, USA

    Jiazhi Sun, De-an Wang, Adam Carie, Steve Paquette, Domenico Coppola & Saïd M Sebti

  3. Department of Chemistry, Yale University, PO Box 208107, New Haven, CT, 06520-8107, USA

    Rishi K Jain, Eileen Ennis, Laura Baldini & Andrew D Hamilton

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  1. Jiazhi Sun
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  2. De-an Wang
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  9. Domenico Coppola
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  10. Andrew D Hamilton
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  11. Saïd M Sebti
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Correspondence to Andrew D Hamilton or Saïd M Sebti.

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Sun, J., Wang, Da., Jain, R. et al. Inhibiting angiogenesis and tumorigenesis by a synthetic molecule that blocks binding of both VEGF and PDGF to their receptors. Oncogene 24, 4701–4709 (2005). https://doi.org/10.1038/sj.onc.1208391

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