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, IL 60064-6121, USA.
Molecular Cancer Therapeutics (Impact Factor: 5.68). 05/2006; 5(4):1007-13. DOI: 10.1158/1535-7163.MCT-05-0359
Source: PubMed


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.

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    • "Linifanib (ABT-869) is an orally active novel small molecule multi-target receptor tyrosine kinase (RTK) inhibitor, which simultaneously inhibits VEGFR and PDGFR with minimal activity against unrelated RTKs. It has potent inhibitory activity against VEGFR-1, VEGFR-2, PDGFRb, colony-stimulating factor 1 receptor, and fms-related tyrosine kinase 3, with minimal activity against unrelated tyrosine and serine/threonine kinases [3-5]. Linifanib has shown prominent antitumor activity against solid tumors in phase 2 studies e.g. "
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    Chemistry Central Journal 02/2014; 8(1):13. DOI:10.1186/1752-153X-8-13 · 2.19 Impact Factor
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    • "Linifanib (ABT-869) is a novel, potent inhibitor with selectivity for the VEGFR and PDGFR family of receptor tyrosine kinases. It has specific inhibitory activity against VEGFR-1, VEGFR-2, PDGFRβ, colony-stimulating factor 1 receptor, and fms-related tyrosine kinase 3, with minimal activity against unrelated tyrosine and serine/threonine kinases [9–11]. In preclinical studies with multiple human tumor xenograft models, linifanib demonstrated potent antiangiogenic and antitumor effects [9–13]. "
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    Cancer Chemotherapy and Pharmacology 03/2012; 69(6):1477-86. DOI:10.1007/s00280-012-1846-6 · 2.77 Impact Factor
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    • "The expression of c-fms in normal tissue, on the other hand, is limited to macrophages, except during pregnancy [105], making it a better target for therapy, although indiscriminate destruction of macrophages can have serious consequences for health, including decreased liver function and vulnerability to infectious diseases. Nevertheless, a number of agents have been developed to specifically target c-fms, as well as some multitargeted agents, showing c-fms inhibition in enzyme and cell-based assays [106]. Currently, three phase 1 clinical trials involving c-fms inhibitors are recruiting patients (NCT01004861, NCT01316822, and NCT01346358) (, "
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    Clinical and Developmental Immunology 11/2011; 2011:565187. DOI:10.1155/2011/565187 · 2.93 Impact Factor
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