Abstract
We describe a two-dimensional thermal proteome profiling strategy that can be combined with an orthogonal chemoproteomics approach to enable comprehensive target profiling of the marketed histone deacetylase inhibitor panobinostat. The N-hydroxycinnamide moiety is identified as critical for potent and tetrahydrobiopterin-competitive inhibition of phenylalanine hydroxylase leading to increases in phenylalanine and decreases in tyrosine levels. These findings provide a rationale for adverse clinical observations and suggest repurposing of the drug for treatment of tyrosinemia.
MeSH terms
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Dose-Response Relationship, Drug
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Hep G2 Cells
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Histone Deacetylase Inhibitors / chemistry
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Histone Deacetylase Inhibitors / pharmacology*
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Humans
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Hydroxamic Acids / chemistry
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Hydroxamic Acids / pharmacology*
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Indoles / chemistry
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Indoles / pharmacology*
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Molecular Structure
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Panobinostat
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Phenylalanine Hydroxylase / antagonists & inhibitors*
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Phenylalanine Hydroxylase / chemistry
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Phenylalanine Hydroxylase / metabolism
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Structure-Activity Relationship
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Temperature*
Substances
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Indoles
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Panobinostat
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Phenylalanine Hydroxylase
Associated data
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PubChem-Substance/316972334
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PubChem-Substance/316972335
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PubChem-Substance/316972336
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PubChem-Substance/316972337
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PubChem-Substance/316972338
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PubChem-Substance/316972339