title: SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors.
abstract: Vascular endothelial growth factor, fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) and their cognate receptor tyrosine kinases are strongly implicated in angiogenesis associated with solid tumors. Using rational drug design coupled with traditional screening technologies, we have discovered SU6668, a novel inhibitor of these receptors. Biochemical kinetic studies using isolated Flk-1, FGF receptor 1, and PDGF receptor beta kinases revealed that SU6668 has competitive inhibitory properties with respect to ATP. Cocrystallographic studies of SU6668 in the catalytic domain of FGF receptor 1 substantiated the adenine mimetic properties of its oxindole core. Molecular modeling of SU6668 in the ATP binding pockets of the FIk-1/KDR and PDGF receptor kinases provided insight to explain the relative potency and selectivity of SU6668 for these receptors. In cellular systems, SU6668 inhibited receptor tyrosine phosphorylation and mitogenesis after stimulation of cells by appropriate ligands. Oral or i.p. administration of SU6668 in athymic mice resulted in significant growth inhibition of a diverse panel of human tumor xenografts of glioma, melanoma, lung, colon, ovarian, and epidermoid origin. Furthermore, intravital multifluorescence videomicroscopy of C6 glioma xenografts in the dorsal skinfold chamber model revealed that SU6668 treatment suppressed tumor angiogenesis. Finally, SU6668 treatment induced striking regression of large established human tumor xenografts. Investigations of SU6668 activity in cancer patients are ongoing in Phase I clinical trials.
authors.affiliation: SUGEN, Inc., San Francisco, California 94080, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Laird
authors.forename: P
authors.initials: P
authors.lastname: Vajkoczy
authors.forename: L K
authors.initials: LK
authors.lastname: Shawver
authors.forename: A
authors.initials: A
authors.lastname: Thurnher
authors.forename: C
authors.initials: C
authors.lastname: Liang
authors.forename: M
authors.initials: M
authors.lastname: Mohammadi
authors.forename: J
authors.initials: J
authors.lastname: Schlessinger
authors.forename: A
authors.initials: A
authors.lastname: Ullrich
authors.forename: S R
authors.initials: SR
authors.lastname: Hubbard
authors.forename: R A
authors.initials: RA
authors.lastname: Blake
authors.forename: T A
authors.initials: TA
authors.lastname: Fong
authors.forename: L M
authors.initials: LM
authors.lastname: Strawn
authors.forename: L
authors.initials: L
authors.lastname: Sun
authors.forename: C
authors.initials: C
authors.lastname: Tang
authors.forename: R
authors.initials: R
authors.lastname: Hawtin
authors.forename: F
authors.initials: F
authors.lastname: Tang
authors.forename: N
authors.initials: N
authors.lastname: Shenoy
authors.forename: K P
authors.initials: KP
authors.lastname: Hirth
authors.forename: G
authors.initials: G
authors.lastname: McMahon
authors.lastname: Cherrington
mesh_terms: D016475:3T3 Cells; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D000078183:Oxindoles; D011422:Propionates; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors; D011975:Receptors, Mitogen / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D000078183:Oxindoles; D011422:Propionates; D011758:Pyrroles; D017468:Receptors, Fibroblast Growth Factor; D017978:Receptors, Growth Factor; D011975:Receptors, Mitogen; C412603:orantinib; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; D040262:Receptors, Vascular Endothelial Growth Factor