Publikationenhttps://hdl.handle.net/20.500.11811/6632024-03-28T17:31:37Z2024-03-28T17:31:37ZPhotocaged Histone Deacetylase Inhibitors as Prodrugs in Targeted Cancer TherapyKraft, FabianHanl, MariaFeller, FelixSchäker-Hübner, LindaHansen, Finnhttps://hdl.handle.net/20.500.11811/108182023-05-02T09:15:36Z2023-02-25T00:00:00ZPhotocaged Histone Deacetylase Inhibitors as Prodrugs in Targeted Cancer Therapy
Kraft, Fabian; Hanl, Maria; Feller, Felix; Schäker-Hübner, Linda; Hansen, Finn
Histone deacetylases (HDACs) play a key role in the control of transcription, cell prolifer-
ation, 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 (I) and VK1
(II). Initial decaging experiments confirmed that the photocaged HDACi pc-I could be deprotected to
its parent inhibitor I. In HDAC inhibition assays, pc-I displayed only low inhibitory activity against
HDAC1 and HDAC6. After irradiation with light, the inhibitory activity of pc-I strongly increased.
Subsequent MTT viability assays, whole-cell HDAC inhibition assays, and immunoblot analysis
confirmed the inactivity of pc-I at the cellular level. Upon irradiation, pc-I demonstrated pronounced
HDAC inhibitory and antiproliferative activities which were comparable to the parent inhibitor I.
Additionally, only phototreated pc-I was able to induce apoptosis in Annexin V/PI and caspase-Glo
3/7 assays, making pc-I a valuable tool for the development of light-activatable HDACi.
2023-02-25T00:00:00Z