Design of growth factor antagonists with antiangiogenic and antitumor properties.
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 (> 400A2) 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 HRGbeta. In nude mouse models GFB-111 also shows significant inhibition of tumor growth and angiogenesis.
Sebti
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Department of Oncology and Biochemistry and Molecular Biology, University of South Florida, Tampa 33612, USA.
Hamilton
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D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D015195:Drug Design; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000378:metabolism / Q000627:therapeutic use*; D011485:Protein Binding; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C415600:GFB 111; D010456:Peptides, Cyclic; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor