Ortho-Hydroxyanilides: Slow-Acting, Selective HDAC1/HDAC2 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.