3‑Hydroxypyridin-2-thione as Novel Zinc Binding Group for Selective Histone Deacetylase Inhibition

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 non...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2013-05, Vol.56 (9), p.3492-3506
Main Authors: Patil, Vishal, Sodji, Quaovi H, Kornacki, James R, Mrksich, Milan, Oyelere, Adegboyega K
Format: Article
Language:English
Subjects:
Apoptosis - drug effects
Cell Line, Tumor
Cell Proliferation - drug effects
Histone Deacetylase Inhibitors - chemistry
Histone Deacetylase Inhibitors - metabolism
Histone Deacetylase Inhibitors - pharmacology
Histone Deacetylases - chemistry
Histone Deacetylases - metabolism
Humans
Intracellular Space - drug effects
Intracellular Space - metabolism
Molecular Docking Simulation
Protein Conformation
Pyridines - chemistry
Pyridines - metabolism
Pyridines - pharmacology
Pyridones - metabolism
Pyridones - pharmacology
Structure-Activity Relationship
Substrate Specificity
Thiones - chemistry
Thiones - metabolism
Thiones - pharmacology
Zinc - metabolism
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm301769u