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

Research output: Contribution to journalArticle

30 Citations (Scopus)

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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Drug Repositioning
Tyrosinemias
Phenylalanine Hydroxylase
Histone Deacetylase Inhibitors
Proteome
Phenylalanine
Tyrosine
Hot Temperature
sapropterin
panobinostat

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Becher, I., Werner, T., Doce, C., Zaal, E. A., Tögel, I., Khan, C. A., ... 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

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

In: Nature Chemical Biology, Vol. 12, No. 11, 01.11.2016, p. 908-910.

Research output: Contribution to journalArticle

Becher, I, Werner, T, Doce, C, Zaal, EA, Tögel, I, Khan, CA, Rueger, A, Muelbaier, M, Salzer, E, Berkers, CR, Fitzpatrick, PF, Bantscheff, M & Savitski, MM 2016, 'Thermal profiling reveals phenylalanine hydroxylase as an off-target of panobinostat', Nature Chemical Biology, vol. 12, no. 11, pp. 908-910. https://doi.org/10.1038/nchembio.2185
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. / Thermal profiling reveals phenylalanine hydroxylase as an off-target of panobinostat. In: Nature Chemical Biology. 2016 ; Vol. 12, No. 11. pp. 908-910.
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