title: AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts.
abstract: The growth of solid tumors is dependent on the continued stimulation of endothelial cell proliferation and migration resulting in angiogenesis. The angiogenic process is controlled by a variety of factors of which the vascular endothelial growth factor (VEGF) pathway and its receptors play a pivotal role. Small-molecule inhibitors of VEGF receptors (VEGFR) have been shown to inhibit angiogenesis and tumor growth in preclinical models and in clinical trials. A novel nicotinamide, AMG 706, was identified as a potent, orally bioavailable inhibitor of the VEGFR1/Flt1, VEGFR2/kinase domain receptor/Flk-1, VEGFR3/Flt4, platelet-derived growth factor receptor, and Kit receptors in preclinical models. AMG 706 inhibited human endothelial cell proliferation induced by VEGF, but not by basic fibroblast growth factor in vitro, as well as vascular permeability induced by VEGF in mice. Oral administration of AMG 706 potently inhibited VEGF-induced angiogenesis in the rat corneal model and induced regression of established A431 xenografts. AMG 706 was well tolerated and had no significant effects on body weight or on the general health of the animals. Histologic analysis of tumor xenografts from AMG 706-treated animals revealed an increase in endothelial apoptosis and a reduction in blood vessel area that preceded an increase in tumor cell apoptosis. In summary, AMG 706 is an orally bioavailable, well-tolerated multikinase inhibitor that is presently under clinical investigation for the treatment of human malignancies.
authors.affiliation: Department of Oncology Research, Amgen, Inc., Thousand Oaks, CA 91320-1799, USA. tonyp@amgen.com
authors.forename: Anthony
authors.initials: A
authors.lastname: Polverino
authors.forename: Angela
authors.initials: A
authors.lastname: Coxon
authors.forename: Charlie
authors.initials: C
authors.lastname: Starnes
authors.forename: Zobedia
authors.initials: Z
authors.lastname: Diaz
authors.forename: Thomas
authors.initials: T
authors.lastname: DeMelfi
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: James
authors.initials: J
authors.lastname: Bready
authors.forename: Juan
authors.initials: J
authors.lastname: Estrada
authors.forename: Russell
authors.initials: R
authors.lastname: Cattley
authors.forename: Stephen
authors.initials: S
authors.lastname: Kaufman
authors.forename: Danlin
authors.initials: D
authors.lastname: Chen
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Gan
authors.forename: Gondi
authors.initials: G
authors.lastname: Kumar
authors.forename: James
authors.initials: J
authors.lastname: Meyer
authors.forename: Sesha
authors.initials: S
authors.lastname: Neervannan
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Alva
authors.forename: Jane
authors.initials: J
authors.lastname: Talvenheimo
authors.forename: Silvia
authors.initials: S
authors.lastname: Montestruque
authors.forename: Andrew
authors.initials: A
authors.lastname: Tasker
authors.forename: Vinod
authors.initials: V
authors.lastname: Patel
authors.forename: Robert
authors.initials: R
authors.lastname: Radinsky
authors.forename: Richard
authors.initials: R
authors.lastname: Kendall
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D002460:Cell Line; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000627:therapeutic use*; D007947:Leukemia, Megakaryoblastic, Acute / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D009841:Oligonucleotides; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D012867:Skin / Q000187:drug effects; D014183:Transplantation, Heterologous; D014471:Umbilical Veins / Q000502:physiology
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D009841:Oligonucleotides; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D019009:Proto-Oncogene Proteins c-kit; D040262:Receptors, Vascular Endothelial Growth Factor; C519562:imetelstat