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

ABSTRACT: 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 opt

SUBMITTER: Hilscher S 

PROVIDER: S-EPMC12573178 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature