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.
Cellzome GmbH, Heidelberg, Germany.|Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
Isabelle
I
Becher
Cellzome GmbH, Heidelberg, Germany.
Thilo
T
Werner
Cellzome GmbH, Heidelberg, Germany.
Carola
C
Doce
Biomolecular Mass Spectrometry and Proteomics, Utrecht University, Utrecht, the Netherlands.
Esther A
http://orcid.org/0000-0001-9890-7345
EA
Zaal
Cellzome GmbH, Heidelberg, Germany.
Ina
I
Tögel
Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas, USA.
Crystal A
CA
Khan
Cellzome GmbH, Heidelberg, Germany.
Anne
A
Rueger
Cellzome GmbH, Heidelberg, Germany.
Marcel
M
Muelbaier
Cellzome GmbH, Heidelberg, Germany.
Elsa
E
Salzer
Biomolecular Mass Spectrometry and Proteomics, Utrecht University, Utrecht, the Netherlands.
Celia R
CR
Berkers
Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas, USA.
Paul F
PF
Fitzpatrick
Cellzome GmbH, Heidelberg, Germany.
Marcus
http://orcid.org/0000-0002-8343-8977
M
Bantscheff
Cellzome GmbH, Heidelberg, Germany.|Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
Mikhail M
MM
Savitski
D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D000077767:Panobinostat; D010651:Phenylalanine Hydroxylase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013696:Temperature
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat; D010651:Phenylalanine Hydroxylase
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