Ortho-Hydroxyanilides: Slow-Acting, Selective Histone Deacetylase 1/2 Inhibitors Suitable for Photocaging Applications

Histone deacetylases (HDACs) regulate gene expression and are promising targets in oncology. Especially the class I isoforms HDAC1 and HDAC2 are overexpressed in Cancer. However, while ortho-aminoanilides with a suitable (het)-aryl substitution are well-characterized HDAC1/HDAC2 inhibitors, the corresponding phenol analogs have not been sufficiently investigated so far. To this end, we compared the ortho-hydroxyanilide derivative ST13 with the pan-HDAC inhibitor vorinostat and Cpd-60, an ortho-aminoanilide with high HDAC1/HDAC2 selectivity. ST13 was further developed into a light-activatable prodrug (ST17) by masking its zinc-binding group with a photoremovable 4,5-dimethoxy-2-nitrobenzyl protecting group. Overall, we verified that ST13 is a selective, slow- and tight-binding HDAC1/HDAC2 Inhibitor with antiproliferative activity. Furthermore, we demonstrated that the light-activatable prodrug ST17 readily releases ST13 upon irradiation, thereby allowing to precisely control its antiproliferative properties. These findings validate ortho-hydroxyanilides as effective HDAC1/HDAC2-selective inhibitors and highlight photocaging as a promising strategy to achieve spatiotemporal control of epigenetic therapies in Cancer.

HDAC inhibitors (HDACi); cancer; epigenetics; histone deacetylase (HDAC); light-activatable drugs; photocaging.