Abstract
Two structurally distinct series of novel, MAPK-activated kinase-2 prevention of activation inhibitors have been discovered by high throughput screening. Preliminary structure-activity relationship (SAR) studies revealed substructural features that influence the selective inhibition of the activation by p38α of the downstream kinase MK2 in preference to an alternative substrate, MSK1. Enzyme kinetics, surface plasmon resonance (SPR), 2D protein NMR, and X-ray crystallography were used to determine the binding mode and the molecular mechanism of action. The compounds bind competitively to the ATP binding site of p38α but unexpectedly with higher affinity in the p38α-MK2 complex compared with p38α alone. This observation is hypothesized to be the origin of the substrate selectivity. The two lead series identified are suitable for further investigation for their potential to treat chronic inflammatory diseases with improved tolerability over previously studied p38α inhibitors.
MeSH terms
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Adenosine Triphosphate / chemistry
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Adenosine Triphosphate / metabolism
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Binding, Competitive
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Cells, Cultured
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Crystallography, X-Ray
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Dose-Response Relationship, Drug
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Drug Discovery
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Enzyme Activation / drug effects
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Humans
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Kinetics
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MAP Kinase Kinase 2 / antagonists & inhibitors*
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MAP Kinase Kinase 2 / chemistry*
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MAP Kinase Kinase 2 / metabolism
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Magnetic Resonance Spectroscopy
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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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Models, Chemical
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Models, Molecular
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Molecular Structure
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Phosphorylation / drug effects
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Protein Binding
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / pharmacology*
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Protein Structure, Tertiary
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Ribosomal Protein S6 Kinases, 90-kDa / antagonists & inhibitors
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Ribosomal Protein S6 Kinases, 90-kDa / chemistry
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Ribosomal Protein S6 Kinases, 90-kDa / metabolism
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Structure-Activity Relationship
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Substrate Specificity
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Surface Plasmon Resonance
Substances
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Protein Kinase Inhibitors
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Adenosine Triphosphate
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Ribosomal Protein S6 Kinases, 90-kDa
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mitogen and stress-activated protein kinase 1
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Mitogen-Activated Protein Kinase 14
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MAP Kinase Kinase 2