Rapid discovery of highly potent and selective inhibitors of histone deacetylase 8 using click chemistry to generate candidate libraries.

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Suzuki T, Ota Y, Ri M, Bando M, Gotoh A, Itoh Y, Tsumoto H, Tatum PR, Mizukami T, Nakagawa H, Iida S, Ueda R, Shirahige K, Miyata N

Rapid discovery of highly potent and selective inhibitors of histone deacetylase 8 using click chemistry to generate candidate libraries.

J Med Chem. 2012 Nov 26;55(22):9562-75. doi: 10.1021/jm300837y. Epub 2012 Nov 12.

PubMed ID
23116147 [ View in PubMed
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Abstract

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 C149 (IC(50) = 0.070 muM), which was more potent than PCI-34058 (6) (IC(50) = 0.31 muM), a known HDAC8 inhibitor. Molecular modeling suggested that the phenylthiomethyl group of C149 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(50) = 3-80 muM). These findings suggest that HDAC8-selective inhibitors have potential as anticancer agents.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
VorinostatHistone deacetylase 1IC 50 (nM)270N/AN/ADetails
VorinostatHistone deacetylase 2IC 50 (nM)780N/AN/ADetails
VorinostatHistone deacetylase 6IC 50 (nM)210N/AN/ADetails