Abstract
Fragment-based screening identified 7-azaindole as a protein kinase B inhibitor scaffold. Fragment elaboration using iterative crystallography of inhibitor-PKA-PKB chimera complexes efficiently guided improvements in the potency and selectivity of the compounds, resulting in the identification of nanomolar 6-(piperidin-1-yl)purine, 4-(piperidin-1-yl)-7-azaindole, and 4-(piperidin-1-yl)pyrrolo[2,3- d]pyrimidine inhibitors of PKBbeta with antiproliferative activity and showing pathway inhibition in cells. A divergence in the binding mode was seen between 4-aminomethylpiperidine and 4-aminopiperidine containing molecules. Selectivity for PKB vs PKA was observed with 4-aminopiperidine derivatives, and the most PKB-selective inhibitor (30-fold) showed significantly different bound conformations between PKA and PKA-PKB chimera.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Binding Sites
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Cell Line, Tumor
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Chromatography, Liquid / methods
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Crystallography, X-Ray
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Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology*
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Humans
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Ligands
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Magnetic Resonance Spectroscopy / methods
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Mass Spectrometry / methods
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Mice
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Microsomes, Liver / chemistry
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Microsomes, Liver / metabolism
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Models, Molecular
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Molecular Structure
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
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Pyrimidines / chemistry*
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Pyrimidines / metabolism
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Pyrimidines / pharmacology*
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Pyrroles / chemistry*
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Pyrroles / metabolism
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Pyrroles / pharmacology*
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Stereoisomerism
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Structure-Activity Relationship
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Substrate Specificity
Substances
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4-(4-chlorobenzyl)-1-(7H-pyrrolo(2,3-d)pyrimidin-4-yl)piperidin-4-amine
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Enzyme Inhibitors
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Ligands
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Pyrimidines
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Pyrroles
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Proto-Oncogene Proteins c-akt
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Cyclic AMP-Dependent Protein Kinases