Thermal profiling reveals phenylalanine hydroxylase as an off-target of panobinostat
A chemoproteomics approach utilizing the thermal shift assay and quantitative MS resulted in the identification of phenylalanine hydroxylase as an off-target of the histone deacetylase inhibitor panobinostat. We describe a two-dimensional thermal proteome profiling strategy that can be combined with...
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Veröffentlicht in: | Nature chemical biology 2016-11, Vol.12 (11), p.908-910 |
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Hauptverfasser: | , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | A chemoproteomics approach utilizing the thermal shift assay and quantitative MS resulted in the identification of phenylalanine hydroxylase as an off-target of the histone deacetylase inhibitor panobinostat.
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
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-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. |
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ISSN: | 1552-4450 1552-4469 |
DOI: | 10.1038/nchembio.2185 |