¹Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Department of Oncology and Biochemistry and Molecular Biology, University of South Florida, Tampa, Florida, FL 33612, USA

²Department of Chemistry, Yale University, New Haven, Connecticut, CT 06511, USA

Correspondence to: SM Sebti

This review describes our recent efforts in the development of novel therapies for cancer. Our primary approach is to design synthetic agents that antagonize the function of growth factors that are critically involved in oncogenesis and angiogenesis. We achieve this by designing synthetic molecules that can recognize the exterior surface of the growth factor and so block the interaction with its receptor tyrosine kinase. A key step is the construction of synthetic agents that contain a large (>400Ų) and functionalized surface area to recognize a complementary surface on the target growth factor. In the course of this work we have discovered a molecule, GFB-111, that binds to PDGF, prevents it from binding to its receptor tyrosine kinase, blocks PDGF-induced receptor autophosphorylation, activation of Erk1 and Erk2 kinases and DNA synthesis. The binding affinity for PDGF is high (IC₅₀=250 nM) and selective over EGF, IGF-1, aFGF, bFGF and HRG. In nude mouse models GFB-111 also shows significant inhibition of tumor growth and angiogenesis. Oncogene (2000) 19, 6566-6573.

platelet-derived growth factor; angiogenesis; oncogenesis; cancer drug discovery