Identification and Structure–Activity Relationship of HDAC6 Zinc-Finger Ubiquitin Binding Domain Inhibitors

HDAC6
plays a central role in the recruitment of protein aggregates
for lysosomal degradation and is a promising target for combination
therapy with proteasome inhibitors in multiple myeloma. Pharmacologically
displacing ubiquitin from the zinc-finger ubiquitin-binding domain
(ZnF-UBD) of HDAC6 is an underexplored alternative to catalytic inhibition.
Here, we present the discovery of an HDAC6 ZnF-UBD-focused chemical
series and its progression from virtual screening hits to low micromolar
inhibitors. A carboxylate mimicking the C-terminal extremity of ubiquitin,
and an extended aromatic system stacking with W1182 and R1155, are
necessary for activity. One of the compounds induced a conformational
remodeling of the binding site where the primary binding pocket opens
up onto a ligand-able secondary pocket that may be exploited to increase
potency. The preliminary structure–activity relationship accompanied
by nine crystal structures should enable further optimization into
a chemical probe to investigate the merit of targeting the ZnF-UBD
of HDAC6 in multiple myeloma and other diseases.