Review
Targeting Class I Histone Deacetylases in a “Complex” Environment

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Trends

All currently licenced HDAC drugs (HDAC inhibitors) are pan-inhibitors that work by targeting the active-site zinc.

HDAC inhibitors are used in the clinic as anticancer therapeutics, but due to their nonselective nature, many patients experience significant side effects.

The focus within the field is turning to the development of isoform-selective HDAC inhibitors to reduce off-target effects experienced by patients.

HDACs 1, 2, and 3 are of particular interest as they are recruited to multiprotein complexes to mediate gene transcription. As part of these complexes, the HDACs become maximally activated, and are targeted to specific genes.

The recruitment of class I HDACs into multiprotein assemblies opens up the possibility of using alternative strategies to develop complex-specific HDAC inhibitors.

Histone deacetylase (HDAC) inhibitors are proven anticancer therapeutics and have potential in the treatment of many other diseases including HIV infection, Alzheimer’s disease, and Friedreich’s ataxia. A problem with the currently available HDAC inhibitors is that they have limited specificity and target multiple deacetylases. Designing isoform-selective inhibitors has proven challenging due to similarities in the structure and chemistry of HDAC active sites. However, the fact that HDACs 1, 2, and 3 are recruited to several large multi-subunit complexes, each with particular biological functions, raises the possibility of specifically inhibiting individual complexes. This may be assisted by recent structural and functional information about the assembly of these complexes. Here, we review the available structural information and discuss potential targeting strategies.

Section snippets

Targeting HDAC Enzymes

Therapeutics that target HDAC enzymes are actively used in the clinic for the treatment of haematological malignancies and have recently been suggested to be useful in the treatment of other diseases including HIV infection 1, 2, 3, 4, 5, 6, 7, 8. However, all currently licenced HDAC inhibitors are pan-inhibitors, that is, drugs that have little or no selectively for the 11 known zinc-dependent HDACs. More selective inhibitors are actively being investigated but have not yet been licenced for

Current HDAC Inhibitors

The major clinical application of HDAC inhibitors has been in the treatment of cancer, where they cause terminal differentiation and apoptosis of cancer cells. Class I HDACs are overexpressed in many different cancers including gastric, breast, colorectal, prostate, and liver cancer, as well as Hodgkin’s lymphoma [13]. The first HDAC inhibitor drug vorinostat (SAHA) was licensed by the US FDA in 2006 for the treatment of cutaneous T cell lymphoma 8, 14. Four further drugs have also been

Structural Insights into Class I HDAC Inhibition

Structural studies have been useful in understanding and refining the mode of inhibitor binding to the active site of class I HDACs. Curiously, the converse is also true, and inhibitors have facilitated our understanding of the structure of HDACs. This seems to be because the HDAC enzymes are stabilised through inhibitor binding, making it possible to trap the enzyme in a fixed conformation suitable for crystallisation.

The first structure of a class I HDAC (HDAC8) was solved >12 years ago [26]

Diversity of Class I HDAC Complexes

Class I HDACs (with the exception of HDAC8; see Box 1) are recruited into multi-subunit complexes through direct interaction with one of at least 17 co-repressor proteins. Apart from SIN3A (switch-independent protein 3A) and SIN3B, these proteins recruit HDACs through a recognisable, but highly diverse ELM2–SANT domain. The ELM2–SANT domain serves as both a recruitment and activation domain for the HDACs. Structural studies have shown that it wraps completely around the HDAC catalytic domain

Strategies to Develop Complex-Specific Inhibitors

As described in the previous section, class I HDAC can be incorporated into markedly different complexes, resulting in discrete biological functions. Recent chemoproteomic studies using tethered HDAC inhibitors, followed by analysis using mass spectrometry, showed that HDAC inhibitor profiles are dependent on the particular complex, and not just the HDAC component 39, 68. These experiments showed that HDAC1 and HDAC2 are not inhibited by either of the benzamide HDAC inhibitors tacedinaline or

Concluding Remarks

Numerous cell-based and whole-animal studies have shown that the different complexes into which class I HDACs are assembled have diverse biological activities that impact physiological and developmental functions. This strongly implies that rather than using inhibitors that target the HDAC enzymes in all these complexes, it would be better to design inhibitors to specific complexes (see Outstanding Questions).

Recent chemoproteomic studies have suggested that this may be easier to achieve than

Conflicts of Interest

The authors declare that there are no known conflicts of interest associated with this publication.

Is there a physiological advantage in targeting specific HDAC complexes?

How redundant are the roles of the individual class I HDAC complexes in gene regulation?

Are there alternative allosteric sites on HDACs that could be used to enhance the isoform-specificity of HDAC inhibitors?

What are the mechanisms for targeting HDAC complexes to the genome and can these be targeted by inhibitors?

Acknowledgements

J.W.R.S. is supported by a Senior Investigator Award (WT100237) from the Wellcome Trust and a Biotechnology and Biological Sciences Research Council Project Grant (BB/J009598/1). J.W.R.S. is a Royal Society Wolfson Research Merit Award Holder.

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    These authors contributed equally to this work.

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