Abstract
Imatinib, dasatinib, sunitinib, CEP-701, and PKC-412, ATP-competitive small molecule inhibitors of type III receptor tyrosine kinases c-KIT and/or FLT3, were evaluated for binding to the closely related receptor, FMS, by docking into models of inactive and active conformations of the FMS kinase domain. To confirm the docking predictions, the drugs were tested for their activity and selectivity in inhibiting cell proliferation and FMS phosphorylation upon stimulation by the FMS ligand, CSF-1. All five drugs inhibited FMS activity. Imatinib, dasatinib and CEP-701 represent three different types of interactions determining drug potency and selectivity.
Crown Copyright 2010. Published by Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Benzamides
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Binding Sites
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Carbazoles / chemistry
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Carbazoles / pharmacology
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Computer Simulation
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Dasatinib
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Drug Design
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Furans
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Humans
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Hydrogen Bonding
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Imatinib Mesylate
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Indoles / chemistry
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Indoles / pharmacology
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Piperazines / chemistry
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Piperazines / pharmacology
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Pyrroles / chemistry
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Pyrroles / pharmacology
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Receptor, Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
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Receptor, Macrophage Colony-Stimulating Factor / metabolism
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Staurosporine / analogs & derivatives
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Staurosporine / chemistry
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Staurosporine / pharmacology
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Sunitinib
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Thiazoles / chemistry
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Thiazoles / pharmacology
Substances
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Benzamides
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Carbazoles
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Furans
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Indoles
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidines
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Pyrroles
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Thiazoles
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Imatinib Mesylate
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lestaurtinib
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Receptor, Macrophage Colony-Stimulating Factor
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Staurosporine
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midostaurin
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Dasatinib
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Sunitinib