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

September 26th, 2016 by Isabelle Becher

Nature Chemical Biology 12, 908 (2016). doi:10.1038/nchembio.2185

Authors: 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

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.

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