SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors

Vascular endothelial growth factor, fibroblast growth factor (FGF), and pla telet-derived growth factor (PDGF) and their cognate receptor tyrosine kina ses are strongly implicated in angiogenesis associated with solid tumors. U sing rational drug design coupled with traditional screening technologies, we have discovered SU6668, a novel inhibitor of these receptors. Biochemica l kinetic studies using isolated Flk-1, FGF receptor 1, and PDGF receptor b eta kinases revealed that SU6668 has competitive inhibitory properties with respect to ATP. Cocrystallographic studies of SU6668 in the catalytic doma in of FGF receptor 1 substantiated the adenine mimetic properties of its ox indole core. Molecular modeling of SU6668 in the ATP binding pockets of the Flk-1/KDR and PDGF receptor kinases provided insight to explain the relati ve potency and selectivity of SU6668 for these receptors. In cellular syste ms, SU6668 inhibited receptor tyrosine phosphorylation and mitogenesis afte r stimulation of cells by appropriate Ligands. Oral or i.p. administration of SU6668 in athymic mice resulted in significant growth inhibition of a di verse panel of human tumor xenografts of glioma, melanoma, lung, colon, ova rian, and epidermoid origin. Furthermore, intravital multifluorescence vide omicroscopy of C6 glioma xenografts in the dorsal skinfold chamber model re vealed that SU6668 treatment suppressed tumor angiogenesis. Finally, SU6668 treatment induced striking regression of large established human tumor xen ografts. Investigations of SU6668 activity in cancer patients are ongoing i n Phase I clinical trials.