1. ¹Drug Discovery Program, H Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, MRC-DRDIS, Tampa, FL 33612, USA
2. ²Departments of Interdisciplinary Oncology and Biochemistry & Molecular Biology, University of South Florida, Tampa, FL 33412, USA
3. ³Department of Chemistry, Yale University, PO Box 208107, New Haven, CT 06520-8107, USA

Correspondence: SM Sebti, E-mail: Sebti@moffitt.usf.edu; AD Hamilton, E-mail: Andew.hamilton@yale.edu

⁴These authors contributed equally to this work

Received 9 June 2004; Accepted 10 September 2004; Published online 16 May 2005.

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.