Medicinal chemistry advances in targeting class I histone deacetylases

• Published in: Exploration of targeted anti-tumor therapy Vol. 4; no. 4; pp. 757 - 779
• Main Authors: Abdallah, Diaaeldin I., de Araujo, Elvin D., Patel, Naman H., Hasan, Lina S., Moriggl, Richard, Krämer, Oliver H., Gunning, Patrick T.
• Format: Journal Article
• Language: English
• Published: Open Exploration Publishing 2023; Open Exploration Publishing Inc
• Subjects: cap group; epigenetic regulation; histone deacetylases; medicinal chemistry; Review; small-molecule inhibitors; zinc-binding group
• ISSN: 2692-3114; 2692-3114
• DOI: 10.37349/etat.2023.00166

Histone deacetylases (HDACs) are a class of zinc (Zn)-dependent metalloenzymes that are responsible for epigenetic modifications. HDACs are largely associated with histone proteins that regulate gene expression at the DNA level. This tight regulation is controlled by acetylation [via histone acetyl transferases (HATs)] and deacetylation (via HDACs) of histone and non-histone proteins that alter the coiling state of DNA, thus impacting gene expression as a downstream effect. For the last two decades, HDACs have been studied extensively and indicated in a range of diseases where HDAC dysregulation has been strongly correlated with disease emergence and progression—most prominently, cancer, neurodegenerative diseases, HIV, and inflammatory diseases. The involvement of HDACs as regulators in these biochemical pathways established them as an attractive therapeutic target. This review summarizes the drug development efforts exerted to create HDAC inhibitors (HDACis), specifically class I HDACs, with a focus on the medicinal chemistry, structural design, and pharmacology aspects of these inhibitors.