Background:
Many human diseases are associated with dysregulation of HDACs. HDAC6
exhibits deacetylase activity not only to histone protein but also to non-histone proteins such as α-
tubulin, HSP90, cortactin, and peroxiredoxin. These unique functions of HDAC6 have gained significant
attention in the medicinal chemistry community in recent years. Thus a great deal of effort has
devoted to developing selective HDAC6 inhibitors for therapy with the hope to minimize the side effects
caused by pan-HDAC inhibition.
Objective:
The review intends to analyze the structural feature of the scaffolds, to provide useful information
for those who are interested in this field, as well as to spark the future design of the new
inhibitors.
Methods:
The primary tool used for patent searching is SciFinder. All patents are retrieved from the
following websites: the World Intellectual Property Organization (WIPO®), the United States Patent
Trademark Office (USPTO®), Espacenet®, and Google Patents. The years of patents covered in this
review are between 2016 and 2019.
Results:
Thirty-six patents from seventeen companies/academic institutes were classified into three
categories based on the structure of ZBG: hydroxamic acid, 1,3,4-oxadiazole, and 1,2,4-oxadiazole.
ZBG connects to the cap group through a linker. The cap group can tolerate different functional groups,
including amide, urea, sulfonamide, sulfamide, etc. The cap group appears to modulate the selectivity
of HDAC6 over other HDAC subtypes.
Conclusion:
Selectively targeting HDAC6 over other subtypes represents two fold advantages: it
maximizes the pharmacological effects and minimizes the side effects seen in pan-HDAC inhibitors.
Many small molecule selective HDAC6 inhibitors have advanced to clinical studies in recent years. We
anticipate the approval of selective HDAC6 inhibitors as therapeutic agents in the near future.
Erratum to ‘Current status in the discovery of dual BET/HDAC inhibitors’ [Bioorganic & Medicinal Chemistry Letters 31 (2020) 127671]
