Abstract
The design, synthesis and utility of fluorescence probes that bind to the DFG-out conformation of p38alpha kinase are described. Probes that demonstrate good affinity for p38alpha, have been identified and one of the probes, PF-04438255, has been successfully used in an high throughput screening (HTS) assay to identify two novel non-classical p38alpha inhibitors. In addition, a cascade activity assay was utilized to validate the selective binding of these non-classical kinase inhibitors to the unactive form of the enzyme.
MeSH terms
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Binding Sites
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Computer Simulation
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Crystallography, X-Ray
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Fluorescent Dyes / chemical synthesis*
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Fluorescent Dyes / chemistry
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Fluorescent Dyes / pharmacology
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High-Throughput Screening Assays
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Kinetics
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Mitogen-Activated Protein Kinase 14 / chemistry
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Mitogen-Activated Protein Kinase 14 / metabolism*
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Naphthalenes / chemistry
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Naphthalenes / pharmacology
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Structure-Activity Relationship
Substances
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Fluorescent Dyes
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Naphthalenes
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Protein Kinase Inhibitors
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Pyrazoles
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Mitogen-Activated Protein Kinase 14
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doramapimod