Abstract
The availability of high quality probes for specific protein targets is fundamental to the investigation of their function and their validation as therapeutic targets. We report the utilization of a dedicated chemoproteomic assay platform combining affinity enrichment technology with high-resolution protein mass spectrometry to the discovery of a novel nicotinamide isoster, the tetrazoloquinoxaline 41, a highly potent and selective tankyrase inhibitor. We also describe the use of 41 to investigate the biology of tankyrase, revealing the compound induced growth inhibition of a number of tumor derived cell lines, demonstrating the potential of tankyrase inhibitors in oncology.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Drug Discovery*
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Drug Screening Assays, Antitumor
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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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Humans
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Ligands
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Models, Molecular
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Molecular Structure
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Quinoxalines / chemical synthesis
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Quinoxalines / chemistry
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Quinoxalines / pharmacology*
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Structure-Activity Relationship
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Tankyrases / antagonists & inhibitors*
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Tankyrases / metabolism
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Ligands
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Quinoxalines
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tetrazoloquinoxaline
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Tankyrases
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TNKS protein, human