Small Molecule Antagonists of the Interaction between the Histone Deacetylase 6 Zinc-Finger Domain and Ubiquitin

Inhibitors of HDAC6 have attractive
potential in numerous cancers.
HDAC6 inhibitors to date target the catalytic domains, but targeting
the unique zinc-finger ubiquitin-binding domain (Zf-UBD) of HDAC6
may be an attractive alternative strategy. We developed X-ray crystallography
and biophysical assays to identify and characterize small molecules
capable of binding to the Zf-UBD and competing with ubiquitin binding.
Our results revealed two adjacent ligand-able pockets of HDAC6 Zf-UBD
and the first functional ligands for this domain.