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

Isabelle Becher1,2, Thilo Werner1, Carola Doce1

  • 1Cellzome GmbH, Heidelberg, Germany.

Nature Chemical Biology
|September 27, 2016
PubMed

Insights

We developed a new method to identify drug targets. This approach revealed that a specific part of panobinostat is key for inhibiting phenylalanine hydroxylase, potentially explaining side effects and suggesting new uses for the drug.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Proteomics

Background:

  • Histone deacetylase inhibitors (HDACi) are an important class of drugs.
  • Panobinostat is a marketed HDACi with known clinical effects.
  • Understanding the precise molecular targets of drugs is crucial for optimizing their use and managing side effects.

Purpose of the Study:

  • To comprehensively profile the targets of panobinostat using a novel proteomic strategy.
  • To elucidate the mechanism underlying panobinostat's effects on amino acid metabolism.
  • To identify potential new therapeutic applications for panobinostat.

Main Methods:

  • Development and application of a two-dimensional thermal proteome profiling (2D-TPP) strategy.
  • Integration of 2D-TPP with an orthogonal chemoproteomics approach.
  • Analysis of drug-target interactions and their downstream metabolic consequences.

Main Results:

  • Identification of phenylalanine hydroxylase (PAH) as a direct target of panobinostat.
  • The N-hydroxycinnamide moiety of panobinostat was found critical for potent, tetrahydrobiopterin-competitive PAH inhibition.
  • Observed increases in phenylalanine and decreases in tyrosine levels in response to panobinostat treatment.

Conclusions:

  • The study provides a detailed molecular mechanism for panobinostat's action, linking its chemical structure to target inhibition and metabolic changes.
  • The findings offer a biochemical rationale for previously observed adverse clinical effects.
  • Repurposing panobinostat for the treatment of tyrosinemia, a metabolic disorder, is suggested based on its effect on phenylalanine and tyrosine levels.

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