title: SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types.
abstract: SU5416, a novel synthetic compound, is a potent and selective inhibitor of the Flk-1/KDR receptor tyrosine kinase that is presently under evaluation in Phase I clinical studies for the treatment of human cancers. SU5416 was shown to inhibit vascular endothelial growth factor-dependent mitogenesis of human endothelial cells without inhibiting the growth of a variety of tumor cells in vitro. In contrast, systemic administration of SU5416 at nontoxic doses in mice resulted in inhibition of subcutaneous tumor growth of cells derived from various tissue origins. The antitumor effect of SU5416 was accompanied by the appearance of pale white tumors that were resected from drug-treated animals, supporting the antiangiogenic property of this agent. These findings support that pharmacological inhibition of the enzymatic activity of the vascular endothelial growth factor receptor represents a novel strategy for limiting the growth of a wide variety of tumor types.
authors.affiliation: SUGEN, Inc., South San Francisco, California 94080, USA. fong@progenitor.com
authors.forename: T A
authors.initials: TA
authors.lastname: Fong
authors.forename: L K
authors.initials: LK
authors.lastname: Shawver
authors.forename: L
authors.initials: L
authors.lastname: Sun
authors.forename: C
authors.initials: C
authors.lastname: Tang
authors.forename: H
authors.initials: H
authors.lastname: App
authors.forename: T J
authors.initials: TJ
authors.lastname: Powell
authors.forename: Y H
authors.initials: YH
authors.lastname: Kim
authors.forename: R
authors.initials: R
authors.lastname: Schreck
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: W
authors.initials: W
authors.lastname: Risau
authors.forename: A
authors.initials: A
authors.lastname: Ullrich
authors.forename: K P
authors.initials: KP
authors.lastname: Hirth
authors.forename: G
authors.initials: G
authors.lastname: McMahon
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002384:Catalysis; D002455:Cell Division / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005910:Glioma / Q000098:blood supply; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D009374:Neoplasms, Experimental / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors*; D011975:Receptors, Mitogen / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D011758:Pyrroles; D017978:Receptors, Growth Factor; D011975:Receptors, Mitogen; C116890:Semaxinib; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor