Thermal profiling reveals phenylalanine hydroxylase as an off target of 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.
Nature chemical biology