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

Abstract

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.

Metastasising Fibroblasts Show an HDAC6-Dependent Increase in Migration Speed and Loss of Directionality Linked to Major Changes in the Vimentin Interactome

“…The focus of this work is to describe how HDAC6 influences the spatial organization of vimentin, and the downstream consequences for intracellular signalling and cell migration-but not on the protein levels of vimentin. HDAC6 is a protein required for the RasV12 oncogene to oncogenically transform cells, and for the formation of aggresomes, cytokinesis and EMT; it is currently a key target for the development of drugs against cancer [19]. The change in cell shape from circular to elongated that accompanies EMT caused by increased levels of vimentin is also observed upon the inhibition of HDAC6 [20].…”

Chasing a Breath of Fresh Air in Cystic Fibrosis (CF): Therapeutic Potential of Selective HDAC6 Inhibitors to Tackle Multiple Pathways in CF Pathophysiology

“… 71 , 72 In this context, recently reported X-ray cocrystal structures of HDAC6 in complex with selective inhibitors will further help refining the design of novel chemical entities with improved potency and selectivity features. 69 , 73 − 76 This Perspective will examine the multifaceted role of HDAC6 in CF and highlight the potential of selective HDAC6 inhibitors as innovative therapeutic options for the treatment of several aspects of this disabling and lethal rare disease.…”

Vorinostat, a histone deacetylase inhibitor, as a potential novel treatment for psoriasis

“…Given HDAC inhibitors anti‐proliferative and pro‐differentiation effects both in vitro and in vivo in various cell types including KCs, 34‐37 they may be of clinical benefit to patients affected chronic immunological (eg systemic lupus erythematosus, multiple sclerosis) and inflammatory diseases including psoriasis 38‐40 …”