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

doi:10.1038/nchembio.2185

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 language	English
Pages (from-to)	908-910
Number of pages	3
Journal	Nature Chemical Biology
Volume	12
Issue number	11
DOIs	https://doi.org/10.1038/nchembio.2185
Publication status	Published - 1 Nov 2016

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title = "Thermal profiling reveals phenylalanine hydroxylase as an off-target of panobinostat",

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.",

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AU - Becher, Isabelle

AU - Werner, Thilo

AU - Doce, Carola

AU - Zaal, Esther A.

AU - Tögel, Ina

AU - Khan, Crystal A.

AU - Rueger, Anne

AU - Muelbaier, Marcel

AU - Salzer, Elsa

AU - Berkers, Celia R.

AU - Fitzpatrick, Paul F.

AU - Bantscheff, Marcus

AU - Savitski, Mikhail M.

PY - 2016/11/1

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AB - 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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JF - Nature Chemical Biology

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ER -

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

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