Abstract
IkappaB kinase beta (IKK-beta) is a serine-threonine protein kinase critically involved in the activation of the transcription factor Nuclear Factor kappa B (NF-kappaB) in response to various inflammatory stimuli. We have identified a small molecule inhibitor of IKK-beta. Optimization of the lead compound resulted in improvements in both in vitro and in vivo potency, and provided IKK-beta inhibitors exhibiting potent activity in an acute cytokine release model (LPS-induced TNFalpha).
MeSH terms
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Animals
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Cell Line
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Chemokine CCL5 / analysis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology*
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Humans
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I-kappa B Kinase
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Inhibitory Concentration 50
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Mice
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / metabolism
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Structure-Activity Relationship
Substances
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Chemokine CCL5
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Enzyme Inhibitors
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Recombinant Proteins
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Protein Serine-Threonine Kinases
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CHUK protein, human
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Chuk protein, mouse
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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Ikbkb protein, mouse
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Ikbke protein, mouse