Substrate-Guided Development of HDAC11-Selective Inhibitors Featuring α‑Amino Amide Zinc-Binding Groups

Histone deacetylases (HDACs) play a pivotal role in various biological pathways and represent interesting drug targets. Therefore, HDAC inhibitors (HDACi) with high isoform selectivity and a zinc-binding group different from hydroxamic acid, because of its low metabolic stability, are required. HDAC11, as a highly potent defatty-acylase, differs from other HDACs in its substrate preference. Starting from this finding, we developed specific inhibitors for HDAC11 based on a peptide containing a fatty-acylated lysine side chain as the selectivity tail. The introduction of different heteroatoms at the fatty acyl residue was used to generate potent zinc-binding groups in combination with the scissile amide bond, as well as to suppress substrate properties of the resulting compounds. Further optimization resulted in a highly potent and selective HDAC11 inhibitor 31, which exhibits low nanomolar inhibition against HDAC11 without targeting other HDACs and is active in cells. The data presented here may help expand the range of zinc-binding groups utilized in HDAC inhibitors. Furthermore, the concept of the selectivity tail was demonstrated to facilitate straightforward access to selective defatty-acylase inhibitors.