Abstract
N-Pyridinylthiophene carboxamide (compound 21) displays activity against peripheral nerve sheath cancer cells and mouse xenografts by an unknown mechanism. Through medicinal chemistry, we identified a more active derivative, compound 9, and found that only analogues with structures similar to nicotinamide retained activity. Genetic screens using compound 9 found that both NAMPT and NMNAT1, enzymes in the NAD salvage pathway, are necessary for activity. Compound 9 is metabolized by NAMPT and NMNAT1 into an adenine dinucleotide (AD) derivative in a cell-free system, cultured cells, and mice, and inhibition of this metabolism blocked compound activity. AD analogues derived from compound 9 inhibit IMPDH in vitro and cause cell death by inhibiting IMPDH in cells. These findings nominate these compounds as preclinical candidates for the development of tumor-activated IMPDH inhibitors to treat neuronal cancers.
MeSH terms
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Animals
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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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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Humans
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IMP Dehydrogenase / antagonists & inhibitors
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IMP Dehydrogenase / metabolism
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Mice
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NAD* / metabolism
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Nerve Sheath Neoplasms / drug therapy
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Nerve Sheath Neoplasms / metabolism
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Nerve Sheath Neoplasms / pathology
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Niacinamide* / analogs & derivatives
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Niacinamide* / chemistry
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Niacinamide* / metabolism
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Niacinamide* / pharmacology
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Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors
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Nicotinamide Phosphoribosyltransferase / metabolism
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Nicotinamide-Nucleotide Adenylyltransferase / antagonists & inhibitors
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Nicotinamide-Nucleotide Adenylyltransferase / metabolism
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Thiophenes* / chemistry
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Thiophenes* / metabolism
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Thiophenes* / pharmacology
Substances
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NAD
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Niacinamide
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Thiophenes
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IMP Dehydrogenase
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Antineoplastic Agents
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Nicotinamide Phosphoribosyltransferase
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Enzyme Inhibitors
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Nicotinamide-Nucleotide Adenylyltransferase