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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
7
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pubmed:dateCreated |
2008-4-4
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:AherneG WynneGW,
pubmed-author:CaldwellJohn JJJ,
pubmed-author:CollinsIanI,
pubmed-author:DaviesThomas GTG,
pubmed-author:DonaldAlastairA,
pubmed-author:GarrettMichelle DMD,
pubmed-author:HunterLisa KLK,
pubmed-author:McHardyTatianaT,
pubmed-author:RaynaudFlorence IFI,
pubmed-author:RowlandsMartin GMG,
pubmed-author:RuddleRuthR,
pubmed-author:TaylorKevinK,
pubmed-author:VerdonkMarcelM,
pubmed-author:WorkmanPaulP
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pubmed:issnType |
Print
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pubmed:day |
10
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pubmed:volume |
51
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
2147-57
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pubmed:dateRevised |
2011-10-14
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pubmed:meshHeading |
pubmed-meshheading:18345609-Animals,
pubmed-meshheading:18345609-Binding Sites,
pubmed-meshheading:18345609-Cell Line, Tumor,
pubmed-meshheading:18345609-Chromatography, Liquid,
pubmed-meshheading:18345609-Crystallography, X-Ray,
pubmed-meshheading:18345609-Cyclic AMP-Dependent Protein Kinases,
pubmed-meshheading:18345609-Enzyme Inhibitors,
pubmed-meshheading:18345609-Humans,
pubmed-meshheading:18345609-Ligands,
pubmed-meshheading:18345609-Magnetic Resonance Spectroscopy,
pubmed-meshheading:18345609-Mass Spectrometry,
pubmed-meshheading:18345609-Mice,
pubmed-meshheading:18345609-Microsomes, Liver,
pubmed-meshheading:18345609-Models, Molecular,
pubmed-meshheading:18345609-Molecular Structure,
pubmed-meshheading:18345609-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:18345609-Pyrimidines,
pubmed-meshheading:18345609-Pyrroles,
pubmed-meshheading:18345609-Stereoisomerism,
pubmed-meshheading:18345609-Structure-Activity Relationship,
pubmed-meshheading:18345609-Substrate Specificity
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pubmed:year |
2008
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pubmed:articleTitle |
Identification of 4-(4-aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as selective inhibitors of protein kinase B through fragment elaboration.
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pubmed:affiliation |
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, U.K.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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