Abstract
Histone deacetylases (HDACs) are epigenetic drug targets that have gained major scientific attention. Inhibition of these important regulatory enzymes is used to treat cancer, and has the potential to treat a host of other diseases. However, currently marketed HDAC inhibitors lack selectivity for the various HDAC isoenzymes. Several studies have shown that HDAC3, in particular, plays an important role in inflammation and degenerative neurological diseases, but the development of selective HDAC3 inhibitors has been challenging. This review provides an up-to-date overview of selective HDAC3 inhibitors, and aims to support the development of novel HDAC3 inhibitors in the future.
Highlights
During the last decades, epigenetics has been established as a crucial factor in cancer and inflammatory diseases [1,2]
The first family consists of Histone deacetylases (HDACs) classes I, II, and IV, and comprises the “classical” zinc-dependent HDACs, while class III consists of the NAD+ -dependent sirtuin (SIRT1-7) family [8,9]
Most of the currently available smallwhich molecule inhibitors share the HDAC inhibitors share same zinc-binding group (ZBG), binds the zinc ion that is located same zinc-binding group (ZBG), which binds the zinc ion that is located in the active site of class in the active site of class I HDACs
Summary
Epigenetics has been established as a crucial factor in cancer and inflammatory diseases [1,2]. Epigenetics encompasses all inheritable changes in gene expression of eukaryotic cells without changes in the genetic code. This process is carried out by a range of mechanisms, an important one being the association of DNA with histone and non-histone proteins, resulting in the formation of chromatin. Acetylation of histones has become a widely studied process in the last decade, as it has been linked to various diseases, such as cancer and inflammation [1,3]. HDACs play an important role in the deacetylation of non-histone proteins, such as α-tubulin, transcription factors, and nuclear transport proteins, and are involved in several signal transduction pathways [8]. To support the development of novel HDAC3 inhibitors, this paper reviews the currently available HDAC3 selective inhibitors, and discusses new directions in the development of selective HDAC3 inhibitors
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