3-Hydroxypyridin-2-thione as novel zinc binding group for selective histone deacetylase inhibition.

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Patil V, Sodji QH, Kornacki JR, Mrksich M, Oyelere AK

3-Hydroxypyridin-2-thione as novel zinc binding group for selective histone deacetylase inhibition.

J Med Chem. 2013 May 9;56(9):3492-506. doi: 10.1021/jm301769u. Epub 2013 Apr 18.

PubMed ID
23547652 [ View in PubMed
]
Abstract

Small molecules bearing hydroxamic acid as the zinc binding group (ZBG) have been the most effective histone deacetylase inhibitors (HDACi) to date. However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety have stimulated research efforts aimed at finding alternative nonhydroxamate ZBGs. We have identified 3-hydroxypyridin-2-thione (3-HPT) as a novel ZBG that is compatible with HDAC inhibition. 3-HPT inhibits HDAC 6 and HDAC 8 with an IC50 of 681 and 3675 nM, respectively. Remarkably, 3-HPT gives no inhibition of HDAC 1. Subsequent optimization led to several novel 3HPT-based HDACi that are selective for HDAC 6 and HDAC 8. Furthermore, a subset of these inhibitors induces apoptosis in various cancer cell lines.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
VorinostatHistone deacetylase 1IC 50 (nM)38N/AN/ADetails
VorinostatHistone deacetylase 6IC 50 (nM)144N/AN/ADetails