Medicinal chemistry advances in targeting class I histone deacetylases

Diaaeldin I Abdallah; Elvin D de Araujo; Naman H Patel; Lina S Hasan; Richard Moriggl; Oliver H Krämer; Patrick T Gunning

doi:10.37349/etat.2023.00166

Medicinal chemistry advances in targeting class I histone deacetylases

Explor Target Antitumor Ther. 2023;4(4):757-779. doi: 10.37349/etat.2023.00166. Epub 2023 Aug 31.

Authors

Diaaeldin I Abdallah^{1

2}, Elvin D de Araujo¹, Naman H Patel¹, Lina S Hasan¹, Richard Moriggl³, Oliver H Krämer⁴, Patrick T Gunning^{1

2}

Affiliations

¹ Department of Chemical & Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario L5L 1C6, Canada.
² Department of Chemistry, University of Toronto, Toronto, Ontario M5S 2E8, Canada.
³ Institute of Animal Breeding and Genetics, University of Veterinary Medicine, 1210 Vienna, Austria.
⁴ Department of Toxicology, University of Mainz Medical Center, 55131 Mainz, Germany.

Abstract

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.

Keywords: Histone deacetylases; cap group; epigenetic regulation; medicinal chemistry; small-molecule inhibitors; zinc-binding group.

Publication types

Review