Histone
deacetylases (HDACs) are essential for maintaining homeostasis
by catalyzing histone deacetylation. Aberrant expression of HDACs
is associated with various human diseases. Although HDAC inhibitors
are used as effective chemotherapeutic agents in clinical practice,
their applications remain limited due to associated side effects induced
by weak isoform selectivity. HDAC6 displays unique structure and cellular
localization as well as diverse substrates and exhibits a wider range
of biological functions than other isoforms. HDAC6 inhibitors have
been effectively used to treat cancers, neurodegenerative diseases,
and autoimmune disorders without exerting significant toxic effects.
Progress has been made in defining the crystal structures of HDAC6
catalytic domains which has influenced the structure-based drug design
of HDAC6 inhibitors. This review summarizes recent literature on HDAC6
inhibitors with particular reference to structural specificity and
functional diversity. It may provide up-to-date guidance for the development
of HDAC6 inhibitors and perspectives for optimization of therapeutic
applications.
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