title: Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases.
abstract: The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are overexpressed and/or activated in a wide variety of human malignancies. Vascular endothelial growth factor (VEGF) receptors are expressed on the surface of vascular endothelial cells and cooperate with Met to induce tumor invasion and vascularization. EXEL-2880 (XL880, GSK1363089) is a small-molecule kinase inhibitor that targets members of the HGF and VEGF receptor tyrosine kinase families, with additional inhibitory activity toward KIT, Flt-3, platelet-derived growth factor receptor beta, and Tie-2. Binding of EXEL-2880 to Met and VEGF receptor 2 (KDR) is characterized by a very slow off-rate, consistent with X-ray crystallographic data showing that the inhibitor is deeply bound in the Met kinase active site cleft. EXEL-2880 inhibits cellular HGF-induced Met phosphorylation and VEGF-induced extracellular signal-regulated kinase phosphorylation and prevents both HGF-induced responses of tumor cells and HGF/VEGF-induced responses of endothelial cells. In addition, EXEL-2880 prevents anchorage-independent proliferation of tumor cells under both normoxic and hypoxic conditions. In vivo, these effects produce significant dose-dependent inhibition of tumor burden in an experimental model of lung metastasis. Collectively, these data indicate that EXEL-2880 may prevent tumor growth through a direct effect on tumor cell proliferation and by inhibition of invasion and angiogenesis mediated by HGF and VEGF receptors.
authors.affiliation: Exelixis, Inc, South San Francisco, California 94083, USA.
authors.forename: Fawn
authors.initials: F
authors.lastname: Qian
authors.forename: Stefan
authors.initials: S
authors.lastname: Engst
authors.forename: Kyoko
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Peiwen
authors.initials: P
authors.lastname: Yu
authors.forename: Kwang-Ai
authors.initials: KA
authors.lastname: Won
authors.forename: Lillian
authors.initials: L
authors.lastname: Mock
authors.forename: Tracy
authors.initials: T
authors.lastname: Lou
authors.forename: Jenny
authors.initials: J
authors.lastname: Tan
authors.forename: Connie
authors.initials: C
authors.lastname: Li
authors.forename: Danny
authors.initials: D
authors.lastname: Tam
authors.forename: Julie
authors.initials: J
authors.lastname: Lougheed
authors.forename: F Michael
authors.initials: FM
authors.lastname: Yakes
authors.forename: Frauke
authors.initials: F
authors.lastname: Bentzien
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Tal
authors.initials: T
authors.lastname: Zaks
authors.forename: Richard
authors.initials: R
authors.lastname: Wooster
authors.forename: Joel
authors.initials: J
authors.lastname: Greshock
authors.forename: Alison H
authors.initials: AH
authors.lastname: Joly
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D000813:Anilides; C544831:GSK 1363089; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D040262:Receptors, Vascular Endothelial Growth Factor