Abstract
High-throughput screening highlighted 9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (1) as an active inhibitor of ubiquitin-specific proteases (USPs), a family of hydrolytic enzymes involved in the removal of ubiquitin from protein substrates. The chemical behavior of compound 1 was examined. Moreover, the synthesis and in vitro evaluation of new compounds, analogues of 1, led to the identification of potent and selective inhibitors of the deubiquitinating enzyme USP8.
MeSH terms
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Crystallography, X-Ray
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Drug Evaluation, Preclinical
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Endopeptidases / metabolism
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Endosomal Sorting Complexes Required for Transport / antagonists & inhibitors*
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Endosomal Sorting Complexes Required for Transport / metabolism
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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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High-Throughput Screening Assays
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Humans
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Indenes / chemistry*
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Indenes / pharmacology
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Molecular Conformation
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Pyrazines / chemical synthesis
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Pyrazines / chemistry*
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Pyrazines / pharmacology
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Ubiquitin Thiolesterase / antagonists & inhibitors*
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Ubiquitin Thiolesterase / metabolism
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Ubiquitin-Specific Peptidase 7
Substances
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9-oxo-9H-indeno(1,2-b)pyrazine-2,3-dicarbonitrile
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Endosomal Sorting Complexes Required for Transport
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Enzyme Inhibitors
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Indenes
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Pyrazines
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Endopeptidases
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USP7 protein, human
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USP8 protein, human
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Ubiquitin Thiolesterase
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Ubiquitin-Specific Peptidase 7