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Research Articles: Therapeutics

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

Cancer Discovery Research (R47J), Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois

Requests for reprints: Patrick A. Marcotte, Cancer Discovery Research (R47J), Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6121. Phone: 847-937-2437; Fax: 847-935-3622. E-mail: pat.a.marcotte{at}abbott.com

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 K_i 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. [Mol Cancer Ther 2006;5(4):1007–13]

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Received 9/ 7/05; revised 12/20/05; accepted 2/21/06.

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