title: Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors.
abstract: The properties of several multitargeted receptor tyrosine kinase inhibitors have been studied for their inhibition of colony-stimulating factor-1 receptor (CSF-1R) signaling. A structurally novel, multitargeted tyrosine kinase inhibitor (ABT-869), imatinib (STI571), and four compounds currently in clinical development (AG013736, BAY 43-9006, CHIR258, and SU11248) were tested for inhibition of CSF-1R signaling in both the enzymatic and cellular assays. ABT-869 showed potent CSF-1R inhibition in both the enzyme and cell-based assays (IC50s < 20 nmol/L). In contrast to a previous report, we have found that imatinib has activity against human CSF-1R in both assays at submicromolar concentrations. In enzyme assays, we have found that the inhibition of CSF-1R by both ABT-869 and imatinib are competitive with ATP, with Ki values of 3 and 120 nmol/L, respectively. SU11248 is a potent inhibitor of CSF-1R in the enzyme assay (IC50 = 7 nmol/L) and inhibits receptor phosphorylation in the cellular assay (IC50 = 61 nmol/L). AG013736 was also a potent inhibitor of CSF-1R in both assays (enzyme, IC50 = 16 nmol/L; cellular, IC50 = 21 nmol/L), whereas BAY 43-9006 is less potent in the enzyme assay (IC50 = 107 nmol/L) than in the cellular system (IC50 = 20 nmol/L). In contrast, we found that CHIR258 had less activity in the cellular assay (IC50 = 535 nmol/L) relative to its enzymatic potency (IC50 = 26 nmol/L). These results show the use of a cell-based assay to confirm the inhibitory activity of lead compounds and drug candidates, such as ABT-869, against the CSF-1R protein in situ.
authors.affiliation: Cancer Discovery Research (R47J), Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6121, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Marcotte
authors.forename: J Owen
authors.initials: JO
authors.lastname: McCall
authors.forename: Yujia
authors.initials: Y
authors.lastname: Dai
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Pease
authors.forename: Michael R
authors.initials: MR
authors.lastname: Michaelides
authors.forename: Steven K
authors.initials: SK
authors.lastname: Davidsen
authors.forename: Keith B
authors.initials: KB
authors.lastname: Glaser
mesh_terms: D016475:3T3 Cells; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D000068877:Imatinib Mesylate; D007191:Indazoles / Q000494:pharmacology*; D007700:Kinetics; D007854:Lead / Q000494:pharmacology; D051379:Mice; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D007191:Indazoles; D010671:Phenylurea Compounds; D010879:Piperazines; D011743:Pyrimidines; D007854:Lead; D000068877:Imatinib Mesylate; D000255:Adenosine Triphosphate; C513486:linifanib; D011505:Protein-Tyrosine Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor