Photocaged Histone Deacetylase Inhibitors as Prodrugs in Targeted Cancer Therapy

Histone deacetylases (HDACs) play a key role in the control of transcription, cell proliferation, and migration. FDA-approved histone deacetylase inhibitors (HDACi) demonstrate clinical efficacy in the treatment of different T-cell lymphomas and multiple myeloma. However, due to unselective inhibiti...

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Bibliographic Details
Published in:Pharmaceuticals (Basel, Switzerland) Switzerland), 2023-02, Vol.16 (3), p.356
Main Authors: Kraft, Fabian B, Hanl, Maria, Feller, Felix, Schäker-Hübner, Linda, Hansen, Finn K
Format: Article
Language:English
Subjects:
Acids
Cancer
Cancer therapies
Care and treatment
Chemical properties
Dosage and administration
Enzyme inhibitors
Enzymes
epigenetics
histone deacetylase
Kinases
Light
Melanoma
photo-activatable
prodrug
Prodrugs
Skin cancer
Structure
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Summary:Histone deacetylases (HDACs) play a key role in the control of transcription, cell proliferation, and migration. FDA-approved histone deacetylase inhibitors (HDACi) demonstrate clinical efficacy in the treatment of different T-cell lymphomas and multiple myeloma. However, due to unselective inhibition, they display a wide range of adverse effects. One approach to avoiding off-target effects is the use of prodrugs enabling a controlled release of the inhibitor in the target tissue. Herein, we describe the synthesis and biological evaluation of HDACi prodrugs with photo-cleavable protecting groups masking the zinc-binding group of the established HDACi DDK137 ( ) and VK1 ( ). Initial decaging experiments confirmed that the photocaged HDACi could be deprotected to its parent inhibitor . In HDAC inhibition assays, displayed only low inhibitory activity against HDAC1 and HDAC6. After irradiation with light, the inhibitory activity of strongly increased. Subsequent MTT viability assays, whole-cell HDAC inhibition assays, and immunoblot analysis confirmed the inactivity of at the cellular level. Upon irradiation, demonstrated pronounced HDAC inhibitory and antiproliferative activities which were comparable to the parent inhibitor . Additionally, only phototreated was able to induce apoptosis in Annexin V/PI and caspase-Glo 3/7 assays, making a valuable tool for the development of light-activatable HDACi.
ISSN:1424-8247
1424-8247
DOI:10.3390/ph16030356