Abstract
Using an NMR-based fragment screening and X-ray crystal structure-based assembly, starting with millimolar ligands for both the catalytic site and the second phosphotyrosine binding site, we have identified a small-molecule inhibitor of protein tyrosine phosphatase 1B with low micromolar inhibition constant, high selectivity (30-fold) over the highly homologous T-cell protein tyrosine phosphatase, and good cellular activity in COS-7 cells.
MeSH terms
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Animals
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Binding Sites
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COS Cells
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Catalytic Domain
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Crystallography, X-Ray
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / metabolism
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Drug Design
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology*
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Models, Molecular
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Molecular Mimicry
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Nuclear Magnetic Resonance, Biomolecular / methods
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Oxamic Acid / analogs & derivatives*
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Oxamic Acid / chemical synthesis
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Oxamic Acid / pharmacology*
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Phosphorylation
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Protein Tyrosine Phosphatase, Non-Receptor Type 1
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Protein Tyrosine Phosphatase, Non-Receptor Type 2
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Protein Tyrosine Phosphatases / antagonists & inhibitors*
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Protein Tyrosine Phosphatases / metabolism
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STAT3 Transcription Factor
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Structure-Activity Relationship
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / metabolism
Substances
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DNA-Binding Proteins
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Enzyme Inhibitors
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STAT3 Transcription Factor
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Trans-Activators
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Protein Tyrosine Phosphatase, Non-Receptor Type 1
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Protein Tyrosine Phosphatase, Non-Receptor Type 2
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Protein Tyrosine Phosphatases
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Oxamic Acid