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.
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.
Polverino
Anthony
A
Department of Oncology Research, Amgen, Inc., Thousand Oaks, CA 91320-1799, USA. tonyp@amgen.com
Coxon
Angela
A
Starnes
Charlie
C
Diaz
Zobedia
Z
DeMelfi
Thomas
T
Wang
Ling
L
Bready
James
J
Estrada
Juan
J
Cattley
Russell
R
Kaufman
Stephen
S
Chen
Danlin
D
Gan
Yongmei
Y
Kumar
Gondi
G
Meyer
James
J
Neervannan
Sesha
S
Alva
Gonzalo
G
Talvenheimo
Jane
J
Montestruque
Silvia
S
Tasker
Andrew
A
Patel
Vinod
V
Radinsky
Robert
R
Kendall
Richard
R
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
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