A patent review of histone deacetylase 6 inhibitors in neurodegenerative diseases (2014-2019)

ABSTRACT

Introduction: Histone deacetylase 6 (HDAC6) is unique in comparison with other zinc-dependent HDAC family members. An increasing amount of evidence from clinical and preclinical research demonstrates the potential of HDAC6 inhibition as an effective therapeutic approach for the treatment of cancer, autoimmune diseases, as well as neurological disorders. The recently disclosed crystal structures of HDAC6-ligand complexes offer further means for achieving pharmacophore refinement, thus further accelerating the pace of HDAC6 inhibitor discovery in the last few years.

Area covered: This review summarizes the latest clinical status of HDAC6 inhibitors, discusses pharmacological applications of selective HDAC6 inhibitors in neurodegenerative diseases, and describes the patent applications dealing with HDAC6 inhibitors from 2014–2019 that have not been reported in research articles.

Expert opinion: Phenylhydroxamate has proven a very useful scaffold in the discovery of potent and selective HDAC6 inhibitors. However, weaknesses of the hydroxamate function such as metabolic instability and mutagenic potential limit its application in the neurological field, where long-term administration is required. The recent invention of oxadiazole-based ligands by pharmaceutical companies may provide a new opportunity to optimize the druglike properties of HDAC6 inhibitors for the treatment of neurodegenerative diseases.

KEYWORDS:

• Α-tubulin acetylation
• mitochondria transport
• arylhydroxamate
• mutagenicity
• oxadiazole

Article highlights

• The discovery of novel HDAC6 inhibitors has become an attractive area of research in the last few years leading to the generation of diverse HDAC6 inhibitors, thus overcoming the selectivity concern of broad spectrum HDAC inhibitors.

• Five HDAC6 inhibitors are being investigated in clinical trials for different types of cancer, autoimmune diseases, and peripheral pain, but none of them has been advanced into the clinic for the treatment of a neurodegenerative disease.

• Only a limited number of candidates have been investigated that show effective results in models of neurodegenerative diseases.

• Arylhydroxamate has been considered the most useful linker and ZBG for discovering selective HDAC6 inhibitors, while toxicity and poor stability remain hurdles in the advancement of hydroxamate HDAC6 inhibitors to the clinical stage.

• Oxadiazole-type ZBGs have been widely applied to the discovery of novel selective HDAC6 inhibitors, which provides an opportunity to refine the ADMET profiles of HDAC6 inhibitors, especially in regard to their possible genotoxicity.

This box summarizes key points contained in the article.

Acknowledgments

The authors thank Dr Werner Tueckmantel for proofreading the article and providing comments.

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 NIH R01NS079183, R43HD093464, and R41AG058283 (AP Kozikowski).