Rapid Discovery of HighlyPotent and Selective Inhibitors of Histone Deacetylase 8 Using ClickChemistry to Generate Candidate Libraries.

To find HDAC8-selective inhibitors, we designed a libraryof HDAC inhibitor candidates, each containing a zinc-binding groupthat coordinates with the active-site zinc ion, linked via a triazolemoiety to a capping structure that interacts with residues on therim of the active site. These compounds were synthesized by usingclick chemistry. Screening identified HDAC8-selective inhibitors including C149(IC50= 0.070 μM), which was more potentthan PCI-34058 (6) (IC50= 0.31 μM),a known HDAC8 inhibitor. Molecular modeling suggested that the phenylthiomethylgroup of C149binds to a unique hydrophobic pocket ofHDAC8, and the orientation of the phenylthiomethyl and hydroxamatemoieties (fixed by the triazole moiety) is important for the potencyand selectivity. The inhibitors caused selective acetylation of cohesinin cells and exerted growth-inhibitory effects on T-cell lymphomaand neuroblastoma cells (GI50= 3–80 μM).These findings suggest that HDAC8-selective inhibitors have potentialas anticancer agents. [ABSTRACT FROM AUTHOR]