Developing selective histone deacetylases (HDACs) inhibitors through ebselen and analogs

Drug Design, Development and Therapy
Yuren WangHaiching Ma

Abstract

Histone deacetylases (HDACs) are key regulators of gene expression in cells and have been investigated as important therapeutic targets for cancer and other diseases. Different subtypes of HDACs appear to play disparate roles in the cells and are associated with specific diseases. Therefore, substantial effort has been made to develop subtype-selective HDAC inhibitors. In an effort to discover existing scaffolds with HDAC inhibitory activity, we screened a drug library approved by the US Food and Drug Administration and a National Institutes of Health Clinical Collection compound library in HDAC enzymatic assays. Ebselen, a clinical safe compound, was identified as a weak inhibitor of several HDACs, including HDAC1, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, and HDAC9 with half maximal inhibitory concentrations approximately single digit of µM. Two ebselen analogs, ebselen oxide and ebsulfur (a diselenide analog of ebselen), also inhibited these HDACs, however with improved potencies on HDAC8. Benzisothiazol, the core structure of ebsulfur, specifically inhibited HDAC6 at a single digit of µM but had no inhibition on other HDACs. Further efforts on structure-activity relationship based on the core structure of ebsulfur led to th...Continue Reading

Citations

Aug 7, 2019·Journal of Biomolecular Structure & Dynamics·Leandro A Alves AvelarKatarina Nikolic
Apr 2, 2021·Archives of Toxicology·Cristina W NogueiraJoão B T Rocha
Jul 25, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Claudio SantiLuca Sancineto
Jul 28, 2021·Cell Chemical Biology·Yuan XiongEric S Fischer
Oct 23, 2019·Journal of Medicinal Chemistry·Ana Carolina RuberteDaniel Plano

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Methods Mentioned

BETA
acetylation
nuclear magnetic resonance
electrophoresis
NMR

Software Mentioned

Envision
GraphPad Prism

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