Aromatic Ring Fluorination Patterns Modulate Inhibitory Potency of Fluorophenylhydroxamates Complexed with Histone Deacetylase 6.

ABSTRACT: Bavarostat (EKZ-001) is a selective inhibitor of histone deacetylase 6 (HDAC6) that contains a meta-fluorophenylhydroxamate Zn²⁺-binding group. The recently determined crystal structure of its complex with HDAC6 from Danio rerio (zebrafish) revealed that the meta-fluoro substituent binds exclusively in an aromatic crevice defined by F583 and F643 rather than being oriented out toward solvent. To explore the binding of inhibitor C-F groups in this fluorophilic crevice, we now report a series of 10 simple fluorophenylhydroxamates bearing one or more fluorine atoms with different substitution patterns. Inhibitory potencies against human and zebrafish HDAC6 range widely from 121 to >30,000 nM. The best inhibitory potency is measured for meta-difluoropheny

SUBMITTER: Watson PR 

PROVIDER: S-EPMC9489680 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature