title: Inhibition of colony-stimulating-factor-1 signaling in vivo with the orally bioavailable cFMS kinase inhibitor GW2580.
abstract: Colony-stimulating-factor-1 (CSF-1) signaling through cFMS receptor kinase is increased in several diseases. To help investigate the role of cFMS kinase in disease, we identified GW2580, an orally bioavailable inhibitor of cFMS kinase. GW2580 completely inhibited human cFMS kinase in vitro at 0.06 microM and was inactive against 26 other kinases. GW2580 at 1 microM completely inhibited CSF-1-induced growth of mouse M-NFS-60 myeloid cells and human monocytes and completely inhibited bone degradation in cultures of human osteoclasts, rat calvaria, and rat fetal long bone. In contrast, GW2580 did not affect the growth of mouse NS0 lymphoblastoid cells, human endothelial cells, human fibroblasts, or five human tumor cell lines. GW2580 also did not affect lipopolysaccharide (LPS)-induced TNF, IL-6, and prostaglandin E2 production in freshly isolated human monocytes and mouse macrophages. After oral administration, GW2580 blocked the ability of exogenous CSF-1 to increase LPS-induced IL-6 production in mice, inhibited the growth of CSF-1-dependent M-NFS-60 tumor cells in the peritoneal cavity, and diminished the accumulation of macrophages in the peritoneal cavity after thioglycolate injection. Unexpectedly, GW2580 inhibited LPS-induced TNF production in mice, in contrast to effects on monocytes and macrophages in vitro. In conclusion, GW2580's selective inhibition of monocyte growth and bone degradation is consistent with cFMS kinase inhibition. The ability of GW2580 to chronically inhibit CSF-1 signaling through cFMS kinase in normal and tumor cells in vivo makes GW2580 a useful tool in assessing the role of cFMS kinase in normal and disease processes.
authors.affiliation: Department of Molecular Pharmacology, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. jamie.g.conway@gsk.com
authors.forename: James G
authors.initials: JG
authors.lastname: Conway
authors.forename: Brad
authors.initials: B
authors.lastname: McDonald
authors.forename: Janet
authors.initials: J
authors.lastname: Parham
authors.forename: Barry
authors.initials: B
authors.lastname: Keith
authors.forename: David W
authors.initials: DW
authors.lastname: Rusnak
authors.forename: Eva
authors.initials: E
authors.lastname: Shaw
authors.forename: Marilyn
authors.initials: M
authors.lastname: Jansen
authors.forename: Peiyuan
authors.initials: P
authors.lastname: Lin
authors.forename: Alan
authors.initials: A
authors.lastname: Payne
authors.forename: Renae M
authors.initials: RM
authors.lastname: Crosby
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Johnson
authors.forename: Lloyd
authors.initials: L
authors.lastname: Frick
authors.forename: Min-Hwa Jasmine
authors.initials: MH
authors.lastname: Lin
authors.forename: Scott
authors.initials: S
authors.lastname: Depee
authors.forename: Sarva
authors.initials: S
authors.lastname: Tadepalli
authors.forename: Bart
authors.initials: B
authors.lastname: Votta
authors.forename: Ian
authors.initials: I
authors.lastname: James
authors.forename: Karen
authors.initials: K
authors.lastname: Fuller
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Chambers
authors.forename: Frederick C
authors.initials: FC
authors.lastname: Kull
authors.forename: Stanley D
authors.initials: SD
authors.lastname: Chamberlain
authors.forename: Jeff T
authors.initials: JT
authors.lastname: Hutchins
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000840:Anisoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D001862:Bone Resorption / Q000517:prevention & control; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C506269:5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine; D000840:Anisoles; D016207:Cytokines; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor