Abstract
The tyrosine kinase p56lck (lck) is essential for T cell activation; thus, inhibitors of lck have potential utility as autoimmune agents. Our initial disclosure of a new class of lck inhibitors based on the phenylaminoimidazoisoquinolin-9-one showed reasonable cellular activity but did not work in vivo upon oral administration. Our current work highlights the further use of rational drug design and molecular modeling to produce a series of lck inhibitors that demonstrate cellular activity below 100 nM and are as efficacious as cyclosporin A in an in vivo mouse model of anti-CD3-induced IL-2 production.
MeSH terms
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Administration, Oral
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Animals
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Antibodies, Monoclonal / pharmacology
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Benzimidazoles / chemical synthesis*
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Benzimidazoles / chemistry
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Benzimidazoles / pharmacology
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CD3 Complex / immunology
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Crystallography, X-Ray
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Female
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Humans
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Immunosuppressive Agents / chemical synthesis*
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Immunosuppressive Agents / chemistry
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Immunosuppressive Agents / pharmacology
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Interleukin-2 / antagonists & inhibitors
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Interleukin-2 / biosynthesis
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Interleukin-2 / blood
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Isoquinolines / chemical synthesis*
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Isoquinolines / chemistry
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Isoquinolines / pharmacology
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Jurkat Cells
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors*
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Mice
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Mice, Inbred BALB C
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Models, Molecular
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Molecular Conformation
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Protein Binding
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Structure-Activity Relationship
Substances
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Antibodies, Monoclonal
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Benzimidazoles
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CD3 Complex
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Enzyme Inhibitors
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Immunosuppressive Agents
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Interleukin-2
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Isoquinolines
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)