HDAC7 Inhibition by Phenacetyl and Phenylbenzoyl Hydroxamates

The zinc-containing histone deacetylase
enzyme HDAC7 is emerging
as an important regulator of immunometabolism and cancer. Here, we
exploit a cavity in HDAC7, filled by Tyr303 in HDAC1, to derive new
inhibitors. Phenacetyl hydroxamates and 2-phenylbenzoyl hydroxamates
bind to Zn2+ and are 50–2700-fold more selective
inhibitors of HDAC7 than HDAC1. Phenylbenzoyl hydroxamates are 30–70-fold
more potent HDAC7 inhibitors than phenacetyl hydroxamates, which is
attributed to the benzoyl aromatic group interacting with Phe679 and
Phe738. Phthalimide capping groups, including a saccharin analogue,
decrease rotational freedom and provide hydrogen bond acceptor carbonyl/sulfonamide
oxygens that increase inhibitor potency, liver microsome stability,
solubility, and cell activity. Despite being the most potent HDAC7
inhibitors to date, they are not selective among class IIa enzymes.
These strategies may help to produce tools for interrogating HDAC7
biology related to its catalytic site.