Detail of "252003-65-9"

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Pharmacological Characterization of CP-547,632, a Novel Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitor for Cancer Therapy

Pharmacological Characterization of CP-547,632, a Novel Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitor for Cancer Therapy. Beebe, Jean S.; Jani, Jitesh P.; Knauth, Elisabeth; Goodwin, Peter; Higdon, Carla; Rossi, Ann Marie; Emerson, Erling; Finkelstein, Martin; Floyd, Eugenia; Harriman, Shawn; Atherton, Jim; Hillerman, Steve; Soderstrom, Cathy; Kou, Kou; Gant, Tom; Noe, Mark C.; Foster, Barb; Rastinejad, Farzan; Marx, Matthew A.; Schaeffer, Tracey; Whalen, Pamela M.; Roberts, W. Gregory (Cancer Drug Discovery, Pfizer Global Research and Development, Groton, CT 06340, USA). Cancer Research, 63(21), 7301-7309 (English) 2003 American Association for Cancer Research. CODEN: CNREA8. ISSN: 0008-5472. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) 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 mol. 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 mol. 386705-49-3 and 252003-65-9 which are cas registry numbers are also used here. inhibitor. A novel isothiazole, CP-547,632, was identified as a potent inhibitor of the VEGFR-2 and basic fibroblast growth factor (FGF kinases) (IC50 = 11 and 9 nM, resp.). It is selective relative to epidermal growth factor receptor, platelet-derived growth factor b, and other related TKs. It also inhibits VEGF-stimulated autophosphorylation of VEGFR-2 in a whole cell assay with an IC50 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 (EC50 = 590 ng/mL). These plasma concns. correlated well with the obsd. concns. of the compd. 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 compd. 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 clin. investigation for the treatment of human malignancies. .