An update on the emerging approaches for histone deacetylase (HDAC) inhibitor drug discovery and future perspectives

ABSTRACT

Introduction

HDACs catalyze the removal of acetyl groups from the ε-N-acetylated lysine residues of various protein substrates including both histone and nonhistone proteins. Different HDACs have distinct biological functions and are recruited to specific regions of the genome. HDAC inhibitors have attracted much attention in recent decades; indeed, there have been more than thirty HDAC inhibitors investigated in clinic trials with five approvals being achieved.

Areas covered

This review covers the emerging approaches for HDAC inhibitor drug discovery from the past five years and includes discussion of structure-based rational design, isoform selectivity, and dual mechanism/multi-targeting. Chemical structures in addition to the in vitro and in vivo inhibiting activity of these compounds have also been discussed.

Expert opinion

The exact role and biological functions of HDACs is still under investigation with a variety of HDAC inhibitors having been designed and evaluated. HDAC inhibitors have shown promise in treating cancer, AD, metabolic disease, viral infection, and multiple sclerosis, but there is still a lot of room for clinical improvement. In the future, more efforts should be put into (i) HDAC isoform identification (ii) the optimization of selectivity, activity, and pharmacokinetics; and (iii) unconventional approaches for discovering different effective scaffolds and pharmacophores.

KEYWORDS:

• Histone deacetylases
• isoform selectivity
• multitargeting agents
• anti-cancer
• rational design

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Article highlights

• HDAC inhibitors have attracted much attention in recent decades. So far there have been more than thirty HDAC inhibitors investigated in clinic trials with five reaching approval.

• Structure-based rational design of HDAC inhibitors mainly include three essential pharmacophores: a zinc binding group (ZBG), a hydrophobic linker and a cap.

• The discovery of isozyme-selective HDAC inhibitors is critical for understanding the biological functions of individual HDACs and for validating HDACs as drug targets.

• Multitargeting agents can simultaneously modulate a network of disease-relevant targets and result in a synergistic effect; they also offer the potential for higher efficacy and less adverse effects.

• While HDAC inhibitors have shown promise in treating cancer, AD, metabolic disease, viral infection, and multiple sclerosis, there is still much room for clinical improvement

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This work was supported by the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (Grant No. 18KJA350001) and the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD).