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

Area of Science:

• Biochemistry and Molecular Biology
• Medicinal Chemistry
• Pharmacology

Background:

• Histone deacetylases (HDACs) are crucial regulators of gene expression and are implicated in various diseases, including cancer.
• Developing subtype-selective HDAC inhibitors is essential due to the diverse roles of different HDACs.
• Existing drug libraries offer potential scaffolds for discovering novel HDAC inhibitors.

Purpose of the Study:

• To identify existing compounds with histone deacetylase (HDAC) inhibitory activity.
• To discover novel, potent, and selective HDAC inhibitors for potential therapeutic applications.

Main Methods:

• Screening of FDA-approved drug libraries and NIH Clinical Collection compounds in HDAC enzymatic assays.
• Structure-activity relationship (SAR) studies based on identified scaffolds.
• In vitro assays to determine inhibitory concentrations (IC50) and target selectivity.
• Cell-based assays measuring α-tubulin acetylation and tumor cell line viability.

Main Results:

• Ebselen was identified as a weak inhibitor of multiple HDACs (HDAC1-9) with IC50 in the µM range.
• Ebselen analogs, ebselen oxide and ebsulfur, also inhibited HDACs, with improved potency against HDAC8.
• Benzisothiazol, a core structure of ebsulfur, selectively inhibited HDAC6.
• SAR studies led to the discovery of RBC-2008, a novel class of potent HDAC6 inhibitors with nM potency.
• RBC-2008 increased α-tubulin acetylation in PC-3 cells and induced dose-dependent cell death in tumor cell lines.

Conclusions:

• Ebselen and its analogs are effective inhibitors of various histone deacetylases (HDACs).
• The ebsulfur scaffold can be optimized to yield potent and selective HDAC6 inhibitors, exemplified by RBC-2008.
• These novel HDAC6 inhibitors demonstrate potential for preclinical development in cancer therapy.