title: Pharmacological characterization of CP-547,632, a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for cancer therapy.
abstract: Signaling through vascular endothelial growth factor (VEGF) receptors (VEGFRs) is a key pathway initiating endothelial cell proliferation and migration resulting in angiogenesis, a requirement for human tumor growth and metastasis. Abrogation of signaling through VEGFR by a variety of approaches has been demonstrated to inhibit angiogenesis and tumor growth. Small molecule inhibitors of VEGFR tyrosine kinase have been shown to inhibit angiogenesis, inhibit tumor growth, and prevent metastases. Our goal was to discover and characterize an p.o. active VEGFR-2 small molecule inhibitor. A novel isothiazole, CP-547,632, was identified as a potent inhibitor of the VEGFR-2 and basic fibroblast growth factor (FGF) kinases (IC(50) = 11 and 9 nM, respectively). It is selective relative to epidermal growth factor receptor, platelet-derived growth factor beta, and other related TKs. It also inhibits VEGF-stimulated autophosphorylation of VEGFR-2 in a whole cell assay with an IC(50) value of 6 nM. After oral administration of CP-547,632 to mice bearing NIH3T3/H-ras tumors, VEGFR-2 phosphorylation in tumors was inhibited in a dose-dependent fashion (EC(50) = 590 ng/ml). These plasma concentrations correlated well with the observed concentrations of the compound necessary to inhibit VEGF-induced corneal angiogenesis in BALB/c mice. A sponge angiogenesis assay was used to directly compare the inhibitory activities of CP-547,632 against FGF receptor 2 or VEGFR-2; this compound potently inhibits both basic FGF and VEGF-induced angiogenesis in vivo. The antitumor efficacy of this agent was evaluated after once daily p.o. administration to athymic mice bearing human xenografts and resulted in as much as 85% tumor growth inhibition. CP-547,632 is a well-tolerated, orally-bioavailable inhibitor presently under clinical investigation for the treatment of human malignancies.
authors: Cancer Drug Discovery, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
authors: Jean S
authors: JS
authors: Beebe
authors: Jitesh P
authors: JP
authors: Jani
authors: Elisabeth
authors: E
authors: Knauth
authors: Peter
authors: P
authors: Goodwin
authors: Carla
authors: C
authors: Higdon
authors: Ann Marie
authors: AM
authors: Rossi
authors: Erling
authors: E
authors: Emerson
authors: Martin
authors: M
authors: Finkelstein
authors: Eugenia
authors: E
authors: Floyd
authors: Shawn
authors: S
authors: Harriman
authors: Jim
authors: J
authors: Atherton
authors: Steve
authors: S
authors: Hillerman
authors: Cathy
authors: C
authors: Soderstrom
authors: Kou
authors: K
authors: Kou
authors: Tom
authors: T
authors: Gant
authors: Mark C
authors: MC
authors: Noe
authors: Barb
authors: B
authors: Foster
authors: Farzan
authors: F
authors: Rastinejad
authors: Matthew A
authors: MA
authors: Marx
authors: Tracey
authors: T
authors: Schaeffer
authors: Pamela M
authors: PM
authors: Whalen
authors: W Gregory
authors: WG
authors: Roberts
mesh_terms: D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C480540:3-(4-bromo-2,6-difluorobenzyloxy)-5-(3-(4-pyrrolidin-1-ylbutyl)ureido)isothiazole-4-carboxylic acid amide; D004791:Enzyme Inhibitors; D013844:Thiazoles; D014508:Urea; D040301:Vascular Endothelial Growth Factor Receptor-2