A Review of Progress in Histone Deacetylase 6 Inhibitors Research: Structural Specificity and Functional Diversity

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.