Histone deacetylase (HDAC) inhibitors in cancer: a patent review (2017-present)

ABSTRACT

Introduction: Histone deacetylase (HDAC) inhibitors play a crucial role in restoring the balance of acetylation and deacetylation of lysine residues of histones and non-histone proteins, which are applied to treat several diseases including cancer.

Area covered: This review covers recent efforts in the synthesis and applications of inhibitors and hybrid inhibitors targeting HDAC from 2017 to 2019.

Expert opinion: HDACs are important epigenetic targets and HDAC inhibitors have become important biologically active compounds for the treatment of cancers. Among the recent patents available, most of them place emphasis on HDAC selective inhibitors and multitarget HDAC inhibitors. Although great accomplishments have been achieved in developing HDAC selective inhibitors, there is still an urgent need for discovery of novel HDAC inhibitors with new zinc-binding groups avoiding the unfavorable pharmacokinetics profiles of hydroxamic acid. Apart from cancer therapy, HDAC inhibitors have recently been considered as a new strategy in treating other human diseases, such as alcohol use disorder (AUD), neurological disorders, age-related diseases, and so forth.

KEYWORDS:

• Histone deacetylases
• inhibitors
• hybrids
• cancer

Article highlights

• Zinc²⁺-dependent HDAC inhibitors are described.

• Several bifunctional HDAC inhibitors are described.

• Most compounds are HDAC6 selective inhibitors.

• Most HDAC inhibitors bear hydroxamic acid as ZBG group.

• HDAC inhibitory activities are generally confirmed by enzymatic assays and several of them are also validated by western blot analysis.

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.

Reviewer disclosures

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

Additional information

Funding

This paper was funded by the Natural Science Foundation of Shandong Province [Grant No. ZR2018QH007]; Key Research and Development Program of Shandong Province [2017CXGC1401]; and the Young Scholars Program of Shandong University [YSPSDU, 2016WLJH33].