Elsevier

Biochemical Pharmacology

Volume 84, Issue 6, 15 September 2012, Pages 756-765
Biochemical Pharmacology

Commentary
Development and therapeutic impact of HDAC6-selective inhibitors

https://doi.org/10.1016/j.bcp.2012.06.014Get rights and content

Abstract

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.

Introduction

Protein lysine acetylation plays a key role in the regulation of fundamental cellular functions. This post-translational modification is a reversible dynamic process regulated by the balance action of histone acetyl-transferases (HAT) and deacetylases (HDAC) [1], [2]. The best known role of protein acetylation is the transcriptional regulation mediated by modulation of histone acetylation status [3], [4]. Indeed, following removal of acetyl groups from histones, HDACs promote chromatin condensation resulting in transcriptional repression. HDACs are implicated in silencing of critical regulatory pathways, including proapoptotic programs. Since epigenetic changes and deregulation of gene expression have been related to malignant behavior and tumor progression, chromatin-modifying enzymes may represent potential therapeutic targets for pharmacological interventions [5].

In addition to histones, specific HDACs are involved in the acetylation status of non-histone proteins including transcription factors (e.g., p53, FOXP3), Hsp90, tubulin and other cytoplasmic proteins that play a role in regulatory processes [1], [6], [7], [8]. Deacetylase-independent functions have been reported for HDAC6 [9]. The interest for HDACs as therapeutic targets stems also from the observation that HDACs may be overexpressed or deregulated in various human tumor types [10], [11]. Given the multiple functions of HDAC isoenzymes and the pleiotropic effects of available HDAC inhibitors, the mechanism of action and the optimal strategy to exploit the therapeutic potential of HDAC inhibitors is not clearly defined. In particular, it is unclear if the isoform selectivity may provide substantial advantages over broad-spectrum inhibition [11]. In spite of the current understanding of the functions of various HDAC family members, the most cancer-relevant isoenzyme as therapeutic target remains to be identified.

The therapeutic potential of HDAC inhibitors has been related to their ability to reactivate silenced tumor suppressor genes and proapoptotic pathways [6]. However, apoptosis may be induced also by HDAC6-selective inhibitors in spite of non-histone deacetylation activity recognized for HDAC6. Most of the known HDAC inhibitors exhibit inhibition against multiple HDAC isoforms, and this broad-spectrum activity may also produce undesirable side effects. Therefore, the development of selective HDAC inhibitors may be useful for better understanding the critical events related to their therapeutic effects and for providing a rational basis to exploit synergistic interactions with other clinically effective agents. Specifically, the implication of HDAC6 in cellular processes relevant to malignant behavior and defence mechanisms of tumor cells has stimulated efforts in an attempt to discover novel selective inhibitors for this isoform. Moreover, the interest for HDAC6 inhibitors is also related to the expected safety profile, because the selective inhibition should avoid toxicity resulting from inhibition of other HDACs [12]. This review focuses on recent advances in the discovery and development of HDAC6-selective inhibitors and their therapeutic applications.

Section snippets

Histone deacetylases: features and functions

Eighteen human enzymes with HDAC activity have been described. The HDAC family members are grouped in four classes on the basis of their homology to yeast HDACs [6], [10]. Class I, II and IV include zinc-dependent enzymes, whereas class III members, known as sirtuins, are NAD+-dependent enzymes. The various classes differ in protein structure, substrate specificity, subcellular localization and tissue expression pattern. Class I HDACs are nuclear enzymes expressed in all tissues, and

Focus on HDAC6-selective inhibitors

A large number of HDAC inhibitors have been identified (Fig. 2). Two inhibitors, vorinostat (SAHA) and romidepsin (depsipeptide, FK228) have been approved for the chemical treatment of cutaneous T-cell lymphoma. A considerable number of inhibitors are currently in clinical development [23]. Most of the known inhibitors are pan-HDAC inhibitors or class I inhibitors [10]. Based on their chemical structure (i.e., the functional zinc-binding group), the available inhibitors can be grouped into

Perspectives in therapeutic applications of HDAC6 inhibitors

The development of isoform-selective inhibitors is expected to provide useful probe inhibitors to explore the functions of individual HDAC enzymes and their role as therapeutic targets. On the basis of its unique structure and function, HDAC6 has emerged as a promising target, because its non-histone substrates play a relevant role in cancer-related processes [13], [14]. In addition, inhibition of HDAC6 is not expected to produce severe toxicity, as documented by the good tolerability of

Conclusions

The increasing interest for HDAC inhibitors stems from the role of enzymes of this family in malignant behavior of tumor cells, neurodegenerative diseases and inflammatory disorders. The evidence that epigenetic deregulation resulting in multiple alterations is implicated in tumor progression has stimulated efforts to develop intervention strategies targeting HDACs. Given the pleiotropic effects of broad spectrum HDAC inhibitors, their use could provide therapeutic effects by simultaneously

Conflicts of interest

C. Pisano is employee of Sigma-Tau. The other authors disclosed no potential conflicts of interest.

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