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Thermal profiling reveals phenylalanine hydroxylase as an off-target of panobinostat
Open accessAbstract
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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“Consider TTC38, for instance, a poorly characterized protein that has been previously identified as an off-target of the HDAC inhibitor panobinostat36 and found herein to display stereoselective interaction with the (S)-4 probe that was blocked by panobinostat.”
From Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs (2019) · cites this paper as [36]
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Metadata
- Authors
- Becher, I., Werner, T., Doce, C., Zaal, E. A., Tögel, I., Khan, C. A., Rueger, A., Muelbaier, M., Salzer, E., Berkers, C. R., Fitzpatrick, P. F., Bantscheff, M., & Savitski, M. M.
- Affiliations
- European Molecular Biology Laboratory (DE)
- Utrecht University (NL)
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Bantscheff, Marcus
- Savitski, Mikhail M
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2016-09-26
- Volume
- 12
- Issue
- 11
- Pages
- 908-910
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W2524972396
- Cited by
- 251
- References
- 30
- Citations by year
- 2026: 19 · 2025: 21 · 2024: 33 · 2023: 30 · 2022: 25 · 2021: 29 · 2020: 41 · 2019: 27 · 2018: 20 · 2017: 5 · 2016: 1
- FWCI
- 8.80
- Type
- journal article
- Language
- en
- Open access
- green
- dspace.library.uu.nl
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Topics
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- phenylalanine hydroxylase, panobinostat, off-target effects, histone deacetylase inhibitors, thermal proteome profiling, chemoproteomics, thermal shift assay, tyrosinemia, drug repurposing, phenylalanine metabolism
- MeSH terms
- Panobinostat, Dose-Response Relationship, Drug, Humans, Hydroxamic Acids, Indoles, Phenylalanine Hydroxylase, Structure-Activity Relationship, Temperature, Molecular Structure, Histone Deacetylase Inhibitors, Hep G2 Cells
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