Source:http://linkedlifedata.com/resource/pubmed/id/19618415
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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
12
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pubmed:dateCreated |
2009-8-17
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pubmed:abstractText |
Kinase inhibitors are increasingly important in drug development. Because the majority of current inhibitors target the conserved ATP-binding site, selectivity might become an important issue. This could be particularly problematic for the potential drug target protein kinase C (PKC), of which twelve isoforms with high homology exist in humans. A strategy to increase selectivity is to prepare bisubstrate-based inhibitors that target the more selective peptide-binding site in addition to the ATP-binding site. In this paper a generally applicable, rapid methodology is presented to discover such bisubstrate-based leads. Dynamic peptide microarrays were used to find peptide-binding site inhibitors. These were linked with chemoselective click chemistry to an ATP-binding site inhibitor, and this led to novel bisubstrate structures. The peptide microarrays were used to evaluate the resulting inhibitors. Thus, novel bisubstrate-based inhibitors were obtained that were both more potent and selective compared to their constituent parts. The most promising inhibitor has nanomolar affinity and selectivity towards PKCtheta amongst three isozymes.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical | |
pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
1439-7633
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pubmed:author | |
pubmed:issnType |
Electronic
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pubmed:day |
17
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pubmed:volume |
10
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
2042-51
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pubmed:meshHeading |
pubmed-meshheading:19618415-Binding Sites,
pubmed-meshheading:19618415-Humans,
pubmed-meshheading:19618415-Isoenzymes,
pubmed-meshheading:19618415-Peptides,
pubmed-meshheading:19618415-Protein Array Analysis,
pubmed-meshheading:19618415-Protein Kinase C,
pubmed-meshheading:19618415-Protein Kinase Inhibitors,
pubmed-meshheading:19618415-Structure-Activity Relationship
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pubmed:year |
2009
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pubmed:articleTitle |
Development of selective bisubstrate-based inhibitors against protein kinase C (PKC) isozymes by using dynamic peptide microarrays.
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pubmed:affiliation |
Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CA, Utrecht (The Netherlands).
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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