Abstract
A novel series of highly potent substituted pyridone Pim-1 kinase inhibitors is described. Structural requirements for in vitro activity are outlined as well as a complex crystal structure with the most potent Pim-1 inhibitor reported (IC(50)=50 nM). A hydrogen bond matrix involving the Pim-1 inhibitor, two water molecules, and the catalytic core, together with a potential weak hydrogen bond between an aromatic hydrogen on the R(1) phenyl ring and a main-chain carbonyl of Pim-1, accounts for the overall potency of this inhibitor.
MeSH terms
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Adenosine Triphosphate / metabolism
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Cloning, Molecular
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Crystallography, X-Ray
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology*
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Humans
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Hydrogen Bonding
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Indicators and Reagents
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Models, Molecular
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Molecular Conformation
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Molecular Sequence Data
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Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-pim-1 / chemical synthesis
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Proto-Oncogene Proteins c-pim-1 / genetics
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Pyridones / chemical synthesis*
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Pyridones / pharmacology*
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Recombinant Proteins / chemistry
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Reverse Transcriptase Polymerase Chain Reaction
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Indicators and Reagents
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Pyridones
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Recombinant Proteins
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Adenosine Triphosphate
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Proto-Oncogene Proteins c-pim-1