Selective histone deacetylase small molecule inhibitors: recent progress and perspectives

ABSTRACT

Introduction: Since the first pan-HDAC inhibitor SAHA was approved by U.S. FDA 10 years ago, HDACs including SIRT1-7 have received significant attention due to the fact that aberrant histone deacetylase activtiy has been implicated in a variety of human diseases, such as cancers, virus infection, and neurodegenerative diseases. During the past years, a considerable achievement of development of isoform- or class-selective HDAC inhibitors has been made, yielding many drug candidates for further clinical studies, which represents a state-of-the-art technology in the drug discovery arena.

Areas covered: This review covers new patents and articles about isoform- or class-selective HDAC inhibitors during the last four years, as well as the therapeutic potential of these compounds.

Expert opinion: HDACs represent one of the most promising therapeutic targets, particularly for tumor therapy though their roles in cancer are still blurry. From 2012 to present, along with the advances of structural biology and homology models, lots of isoform- or class-selective HDAC inhibitors, such as hydroxamic acids and benzamides with various capping groups were found, providing a promising way to circumvent drug toxicity and side-effect issues, as well as providing chemical probes for further better understanding of the biological process related to specific isoform.

KEYWORDS:

• Histone deacetylases
• sirtuin
• selective inhibitors
• anti-cancer
• epigenetics

Article highlights

• HDACs represent a class of promising therapeutic targets, particularly for the treatment of cancers.

• The patents and articles in the field of selective HDAC inhibitors from 2012 to present are summarized.

• Series of selective inhibitors targeting Zn-dependent HDACs or NAD⁺-dependent HDACs (sirtuins) were covered and the biological evaluations indicated that some of the compounds exhibited potential for the treatment of cancers and neurodegenerative diseases.

• A great number of compounds bearing a zinc ion binding group (ZBG) including hydroxamic acids, benzamides and cyclic peptides were described as selective HDAC inhibitors, particularly as HDAC1-, 2-, 3-, 6-, and/or 8-selective inhibitors. Some of the compounds are reported in the progress of clinical trials.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 21302134), the Natural Science Foundation of Jiangsu Province (Grant No. BK20130338), the Suzhou Science & Technology Foundation (Grant No. SYS201665) and PAPD (A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions).