Thermal profiling reveals phenylalanine hydroxylase as an off-target of panobinostat

Isabelle Becher, Thilo Werner, Carola Doce, Esther A. Zaal, Ina Tögel, Crystal A. Khan, Anne Rueger, Marcel Muelbaier, Elsa Salzer, Celia R. Berkers, Paul F Fitzpatrick, Marcus Bantscheff, Mikhail M. Savitski

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54 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)908-910
Number of pages3
JournalNature Chemical Biology
Volume12
Issue number11
DOIs
StatePublished - Nov 1 2016

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Becher, I., Werner, T., Doce, C., Zaal, E. A., Tögel, I., Khan, C. A., Rueger, A., Muelbaier, M., Salzer, E., Berkers, C. R., Fitzpatrick, P. F., Bantscheff, M., & Savitski, M. M. (2016). Thermal profiling reveals phenylalanine hydroxylase as an off-target of panobinostat. Nature Chemical Biology, 12(11), 908-910. https://doi.org/10.1038/nchembio.2185