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 <b>31</b>, 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.