A novel orally bioavailable inhibitor of kinase insert domain-containing receptor induces antiangiogenic effects and prevents tumor growth in vivo.
A strategy for antagonizing vascular endothelial growth factor (VEGF) -induced angiogenesis is to inhibit the kinase activity of its receptor, kinase insert domain-containing receptor (KDR), the first committed and perhaps the last unique step in the VEGF signaling cascade. We synthesized a novel ATP-competitive KDR tyrosine kinase inhibitor that potently suppresses human and mouse KDR activity in enzyme (IC(50) = 7.8-19.5 nM) and cell-based assays (IC(50) = 8 nM). The compound was bioavailable in vivo, leading to a dose-dependent decrease in basal- and VEGF-stimulated KDR tyrosine phosphorylation in lungs from naïve and tumor-bearing mice (IC(50) = 23 nM). Pharmacokinetics and pharmacodynamics guided drug dose selection for antitumor efficacy studies. HT1080 nude mice xenografts were treated orally twice daily with vehicle, or 33 or 133 mg/kg of compound. These doses afforded trough plasma concentrations approximately equal to the IC(50) for inhibition of KDR autophosphorylation in vivo for the 33 mg/kg group, and higher than the IC(99) for the 133 mg/kg group. Chronic treatment at these doses was well-tolerated and resulted in dose-dependent inhibition of tumor growth, decreased tumor vascularization, decreased proliferation, and enhanced cell death. Antitumor efficacy correlated with inhibition of KDR tyrosine phosphorylation in the tumor, as well as in a surrogate tissue (lung). Pharmacokinetics and pharmacodynamics assessment indicated that the degree of tumor growth inhibition correlated directly with the extent of inhibition of KDR tyrosine phosphorylation in tumor or lung at trough. These observations highlight the need to design antiangiogenic drug regimens to ensure constant target suppression and to take advantage of PD end points to guide dose selection.
Sepp-Lorenzino
Laura
L
Department of Cancer Research, Merck Research Laboratories, Merck and Co., Inc., West Point, Pennsylvania, USA. laura_sepplorenzino@merck.com
Rands
Elaine
E
Mao
Xianzhi
X
Connolly
Brett
B
Shipman
Jennifer
J
Antanavage
Joanne
J
Hill
Susan
S
Davis
Lenora
L
Beck
Stephen
S
Rickert
Keith
K
Coll
Kathleen
K
Ciecko
Patrice
P
Fraley
Mark
M
Hoffman
William
W
Hartman
George
G
Heimbrook
David
D
Gibbs
Jackson
J
Kohl
Nancy
N
Thomas
Kenneth
K
D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001682:Biological Availability; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2