Off-target binding of the histone deacetylase inhibitor vorinostat to carbonic anhydrase II and IX.

ABSTRACT: Histone deacetylase inhibitors (HDACi) are widely used in cancer therapy but often suffer from off-target effects due to their pan-inhibitory activity towards zinc-dependent enzymes. Vorinostat (SAHA), a hydroxamate-based HDACi, has been shown to lack isoform selectivity, potentially leading to unintended interactions with other metalloenzymes. Here, we report high-resolution crystal structures of SAHA bound to human carbonic anhydrase II (CA II) and a carbonic anhydrase IX (CA IX) active-site mimic. Structures determined at room temperature and 100 K revealed two distinct SAHA conformers in both CA II and the CA IX mimic, with the hydroxamate moiety displacing the zinc-bound water and adopting either a tetrahedral or pentahedral coordination to Zn2+. Differences in hydrophobic interaction

SUBMITTER: Gulkis MC 

PROVIDER: S-EPMC12400194 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature