Design of growth factor antagonists with antiangiogenic and antitumor properties

This review describes our recent efforts in the development of novel therap ies for cancer. Our primary approach is to design synthetic agents that ant agonize the function of growth factors that are critically involved in onco genesis and angiogenesis. We achieve this by designing synthetic molecules that can recognize the exterior surface of the growth factor and so block t he interaction with its receptor tyrosine kinase, A key step is the constru ction of synthetic agents that contain a large (>400 Angstrom (2)) and func tionalized surface area to recognize a complementary surface on the target growth factor. In the course of this work,ve have discovered a molecule, GF B-111, that binds to PDGF, prevents it from binding to its receptor tyrosin e kinase, blocks PDGF-induced receptor autophosphorylation, activation of E rk1 and Erk2 kinases and DNA synthesis, The binding affinity for PDGF is hi gh (IC50=250 nM) and selective over EGF, IGF-1, aFGF, bFGF and HRG beta, In nude mouse models GFB-111 also shows significant inhibition of tumor growt h and angiogenesis.