Abstract
Protein kinase inhibitors have applications as anticancer therapeutic agents and biological tools in cell signaling. Based on a phosphoryl transfer mechanism involving a dissociative transition state, a potent and selective bisubstrate inhibitor for the insulin receptor tyrosine kinase was synthesized by linking ATPgammaS to a peptide substrate analog via a two-carbon spacer. The compound was a high affinity competitive inhibitor against both nucleotide and peptide substrates and showed a slow off-rate. A crystal structure of this inhibitor bound to the tyrosine kinase domain of the insulin receptor confirmed the key design features inspired by a dissociative transition state, and revealed that the linker takes part in the octahedral coordination of an active site Mg2+. These studies suggest a general strategy for the development of selective protein kinase inhibitors.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenosine Triphosphate / analogs & derivatives*
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Adenosine Triphosphate / metabolism
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Animals
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Binding Sites
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Catalytic Domain
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Chickens
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Crystallography, X-Ray
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Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Drug Design*
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / metabolism*
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Hydrogen Bonding
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Kinetics
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Magnesium / metabolism
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Models, Molecular
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Peptides / chemistry
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Peptides / metabolism
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Phosphorylation
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Protein Binding
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Protein Structure, Tertiary
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Receptor, Insulin / antagonists & inhibitors*
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Receptor, Insulin / chemistry
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Receptor, Insulin / metabolism*
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Substrate Specificity
Substances
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Enzyme Inhibitors
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Peptides
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adenosine 5'-O-(3-thiotriphosphate)
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Adenosine Triphosphate
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Receptor, Insulin
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Cyclic AMP-Dependent Protein Kinases
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Magnesium