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

Year: 2025

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide 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.

Source: ACS Pharmacology & Translational Science

DOI: 10.1021/acsptsci.5c00562

Authors: Irina Honin, Tao Sun, Nisha Setia, Linda Schäker-Hübner, Finn K. Hansen

Institution: University of Bonn

Language: English

Topic: Histone Deacetylase Inhibitors Research

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,500