Unique Molecular Interaction with the Histone Deacetylase 6 Catalytic Tunnel: Crystallographic and Biological Characterization of a Model Chemotype

Histone deacetylase 6 (HDAC6) is
involved in multiple regulatory
processes, ranging from cellular stress to intracellular transport.
Inhibition of aberrant HDAC6 activity in several cancers and neurological
diseases has been shown to be efficacious in both preclinical and
clinical studies. While selective HDAC6 targeting has been pursued
as an alternative to pan-HDAC drugs, identifying truly selective molecular
templates has not been trivial. Herein, we report a structure–activity
relationship study yielding TO-317, which potently binds
HDAC6 catalytic domain 2 (Ki = 0.7 nM)
and inhibits the enzyme function (IC50 = 2 nM). TO-317 exhibits 158-fold selectivity for HDAC6 over other HDAC isozymes
by binding the catalytic Zn2+ and, uniquely, making a never
seen before direct hydrogen bond with the Zn2+ coordinating
residue, His614. This novel structural motif targeting the second-sphere
His614 interaction, observed in a 1.84 Å resolution crystal structure
with drHDAC6 from zebrafish, can provide new pharmacophores
for identifying enthalpically driven, high-affinity, HDAC6-selective
inhibitors.