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
Hauptverfasser: Becher, Isabelle, Werner, Thilo, Doce, Carola, Zaal, Esther A, Tögel, Ina, Khan, Crystal A, Rueger, Anne, Muelbaier, Marcel, Salzer, Elsa, Berkers, Celia R, Fitzpatrick, Paul F, Bantscheff, Marcus, Savitski, Mikhail M
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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 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.
ISSN:1552-4450
1552-4469
DOI:10.1038/nchembio.2185