Histone Acetyltransferase and Deacetylase Inhibitors - New Aspects and Developments

Dear Colleagues,

Epigenetic processes modulate gene transcription and genomic stability, ensuring proper cell development and differentiation. Epigenetic processes are controlled, among other things, by post-translational modifications on histones, acetylation being a highly abundant example of these modifications. Acetylation patterns on histones are regulated by the synergy between a group of epigenetic enzymes, histone acetyltransferase enzymes (HATs), which introduce the modification, and a group that removes the modification, named histone deacetylases (HDACs). Histone deacetylases, in particular, have come into focus for drug discovery in recent years, and the first five inhibitors have been approved for cancer therapy. Although these compounds are non-selective HDAC inhibitors, current research is focused on developing selective inhibitors of the 18 HDAC subtypes. In particular, the recently explored subtypes, such as HDAC10, HDAC11, or the sirtuins, represent new targets for putative drugs. The availability of crystal structures for most of the HDACs also enables the application of in silico and structure-based approaches to drug discovery. In the case of histone acetyltransferases, much fewer inhibitor discovery studies have been reported so far.

A completely new approach is the inhibition of physiological processes by protein degradation. This can be achieved with so-called proteolysis targeting chimera (PROTACs) or molecular glues. PROTACs are heterobifunctional molecules that couple a target ligand with a ligand for an E3 ligase so that the enzyme is polyubiquitinated and degraded by the proteasome. For HDACs, the PROTAC field is still in its infancy, although the first compounds have recently been reported.

The aim of this Special Issue is to highlight the current efforts and new results in medicinal chemistry, in silico studies, and biological characterization of histone deacetylase and acetyltransferase inhibitors. Original research articles, review articles, and short communications in the research areas described (but not limited to) are welcome.

Prof. Dr. Wolfgang Sippl
Dr. Hany S. Ibrahim
Guest Editors

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• histone acetyltransferase enzymes (HATs)
• histone deacetylases (HDACs)
• HDAC inhibitors