1 research outputs found
Rapid Discovery of Highly Potent and Selective Inhibitors of Histone Deacetylase 8 Using Click Chemistry to Generate Candidate Libraries
To find HDAC8-selective inhibitors, we designed a library
of HDAC inhibitor candidates, each containing a zinc-binding group
that coordinates with the active-site zinc ion, linked via a triazole
moiety to a capping structure that interacts with residues on the
rim of the active site. These compounds were synthesized by using
click chemistry. Screening identified HDAC8-selective inhibitors including <b>C149</b> (IC<sub>50</sub> = 0.070 μM), which was more potent
than PCI-34058 (<b>6</b>) (IC<sub>50</sub> = 0.31 μM),
a known HDAC8 inhibitor. Molecular modeling suggested that the phenylthiomethyl
group of <b>C149</b> binds to a unique hydrophobic pocket of
HDAC8, and the orientation of the phenylthiomethyl and hydroxamate
moieties (fixed by the triazole moiety) is important for the potency
and selectivity. The inhibitors caused selective acetylation of cohesin
in cells and exerted growth-inhibitory effects on T-cell lymphoma
and neuroblastoma cells (GI<sub>50</sub> = 3–80 μM).
These findings suggest that HDAC8-selective inhibitors have potential
as anticancer agents