Development and therapeutic impact of HDAC6-selective inhibitors

Histone deacetylases (HDAC) play a key role in regulating gene expression by deacetylating histones. Some HDAC isoforms can also modulate the function of nonhistone proteins implicated in regulatory processes, and therefore HDACs are recognized as useful targets for therapeutic purposes. HDAC inhibitors have generated substantial interest as antitumor agents, because they induce various cellular effects, including apoptosis, cell cycle arrest and inhibition of angiogenesis. The nature of cellular response likely depends on the biological context and on the pattern of HDAC isoform inhibition. Various HDAC inhibitors belonging to different structural classes have been developed. Many inhibitors are characterized by a pan-HDAC inhibitory profile. The potential advantages of isoform-selective inhibitors over pan-HDAC inhibitors in terms of efficacy or toxicity remain to be defined. The emerging interest for HDAC6-selective inhibitors is related to the modulation of acetylation of nonhistone regulatory proteins implicated in cancer-relevant processes, including cell migration, metastasis, angiogenesis and stress-response pathways. This review is focused on the recent development of HDAC inhibitors, with particular reference to HDAC6-selective inhibitors, and the efforts and perspectives in optimization of their therapeutic applications.