Abstract
In this study we report on the specificity profiling of the MAP kinase inhibitors 1, 2, and 3 in a panel of 78 protein kinases including the MAPK isoforms p38(alpha,beta,gamma,delta), JNK1/2/3, and ERK1/2/8 showing 3-(4-fluorophenyl)-4-pyridin-4-ylquinolin-2(1H)-one (1) to be highly selective for p38alphaMAPK with an IC(50) of 1.8 microM. In contrast, besides p38alpha the isoxazoles 2 and 3 significantly inhibited JNK2/3 and further kinases beyond the MAPK family such as PKA, PKD, Lck, and CK1. By using sequence alignment and homology models of different members of the MAPK family the binding mode determining selectivity of 1 for the p38alpha isoform was investigated. For lead optimization of 1 a straightforward tandem-Buchwald-aldol synthetic approach toward the flexible decoration of the quinolin-2(1H)-one scaffold was employed. SAR for derivatives of 1 at the isolated p38alphaMAPK are presented.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Binding Sites
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Biphenyl Compounds / chemistry
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Biphenyl Compounds / pharmacology*
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Humans
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Hydrogen Bonding
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Inhibitory Concentration 50
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Isoenzymes
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Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase 14 / chemistry
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Mitogen-Activated Protein Kinase 14 / metabolism
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / chemistry
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Mitogen-Activated Protein Kinases / metabolism
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Models, Molecular
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology*
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Quinolones / chemistry*
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Quinolones / pharmacology*
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Structure-Activity Relationship
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Substrate Specificity
Substances
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Biphenyl Compounds
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Isoenzymes
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Protein Kinase Inhibitors
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Quinolones
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Adenosine Triphosphate
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Mitogen-Activated Protein Kinase 14
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Mitogen-Activated Protein Kinases