Abstract
A new class of serine/threonine protein kinase inhibitors was designed by associating, in the same structure, mimics of both the ATP binding site and a protein substrate. Among the several potent antagonists which were obtained, the most active consists of isoquinoline-5-sulfonamide, as ATP mimic, and Ser-Arg6, as peptidic moiety, bound by a-NH(CH2)2NH(CH2)2CO-linker. This compound, with a Ki of 0.1 microM toward protein kinase C (PKC) and 0.004 microM toward cyclic AMP dependent protein kinase (PKA), is respectively 60- and 750-fold more active than the commercial inhibitor H-7.
MeSH terms
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Adenosine Triphosphate / analogs & derivatives*
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Adenosine Triphosphate / metabolism
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Binding Sites
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Isoquinolines / chemical synthesis*
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Isoquinolines / chemistry
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Isoquinolines / pharmacology
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Kinetics
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Molecular Structure
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Protein Kinase C / antagonists & inhibitors*
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Protein Kinase Inhibitors*
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Structure-Activity Relationship
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Substrate Specificity
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacology
Substances
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Enzyme Inhibitors
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Isoquinolines
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Protein Kinase Inhibitors
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Sulfonamides
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Adenosine Triphosphate
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Protein Kinase C