Role of Fluorination in the Histone Deacetylase 6 (HDAC6) Selectivity of Benzohydroxamate-Based Inhibitors
Nonselective histone deacetylase (HDAC) inhibitors often face dose-limiting side effects because they inhibit multiple crucial HDAC subtypes. This issue can potentially be mitigated by enhancing their selectivity. In this study, we present the crystal structures of the zebrafish HDAC6 catalytic domain 2 (zHDAC6-CD2) in complex with the selective HDAC6 inhibitors ITF3756 and ITF3985. Our findings reveal how fluorination impacts the selectivity of benzohydroxamate-based inhibitors towards class I isoforms. Specifically, the increased selectivity of these compounds is attributed to unique interactions between the fluorinated linker and key residues Gly582, Ser531, and His614 in zHDAC6. In contrast, these interactions are obstructed in class I HDAC isoforms due to the presence of an Aspartate that replaces Ser531. These insights are valuable for designing and developing new, highly selective HDAC6 inhibitors.