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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Histone Deacetylase Inhibitors / chemistry
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Histone Deacetylase Inhibitors / metabolism*
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Histone Deacetylase Inhibitors / pharmacology*
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Histone Deacetylases / chemistry*
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Histone Deacetylases / metabolism*
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Humans
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Intracellular Space / drug effects
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Intracellular Space / metabolism
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Molecular Docking Simulation
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Protein Conformation
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Pyridines / chemistry
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Pyridines / metabolism*
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Pyridines / pharmacology*
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Pyridones / metabolism
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Pyridones / pharmacology
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Structure-Activity Relationship
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Substrate Specificity
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Thiones / chemistry
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Thiones / metabolism*
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Thiones / pharmacology*
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Zinc / metabolism*
Substances
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Histone Deacetylase Inhibitors
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Pyridines
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Pyridones
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Thiones
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3-hydroxypyridin-2-one
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Histone Deacetylases
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Zinc