title: A novel orally bioavailable inhibitor of kinase insert domain-containing receptor induces antiangiogenic effects and prevents tumor growth in vivo.
abstract: 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.
authors.affiliation: Department of Cancer Research, Merck Research Laboratories, Merck and Co., Inc., West Point, Pennsylvania, USA. laura_sepplorenzino@merck.com
authors.forename: Laura
authors.initials: L
authors.lastname: Sepp-Lorenzino
authors.forename: Elaine
authors.initials: E
authors.lastname: Rands
authors.forename: Xianzhi
authors.initials: X
authors.lastname: Mao
authors.forename: Brett
authors.initials: B
authors.lastname: Connolly
authors.forename: Jennifer
authors.initials: J
authors.lastname: Shipman
authors.forename: Joanne
authors.initials: J
authors.lastname: Antanavage
authors.forename: Susan
authors.initials: S
authors.lastname: Hill
authors.forename: Lenora
authors.initials: L
authors.lastname: Davis
authors.forename: Stephen
authors.initials: S
authors.lastname: Beck
authors.forename: Keith
authors.initials: K
authors.lastname: Rickert
authors.forename: Kathleen
authors.initials: K
authors.lastname: Coll
authors.forename: Patrice
authors.initials: P
authors.lastname: Ciecko
authors.forename: Mark
authors.initials: M
authors.lastname: Fraley
authors.forename: William
authors.initials: W
authors.lastname: Hoffman
authors.forename: George
authors.initials: G
authors.lastname: Hartman
authors.forename: David
authors.initials: D
authors.lastname: Heimbrook
authors.forename: Jackson
authors.initials: J
authors.lastname: Gibbs
authors.forename: Nancy
authors.initials: N
authors.lastname: Kohl
authors.forename: Kenneth
authors.initials: K
authors.lastname: Thomas
mesh_terms: 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
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2