Histone deacetylase inhibitors: Redefining pharmaceutical approaches to the treatment of cancer

The exponential growth in the level of research activity surrounding the histone deacetylases (HDACs) witnessed over the past decade has been driven by the ability of HDAC inhibitors to modulate transcriptional activity. As a result, this therapeutic class is able to block angiogenesis and cell cycling, and promote apoptosis and differentiation. By targeting these key components of tumor proliferation, HDAC inhibitors have the potential to occupy an indomitable position in the fast-moving cytostatic market. Two major reasons why HDAC inhibitors could play such a key role in this $2 billion market are that they are able to improve the efficacy of existing cytostatics (such as the retinoids) and moreover, for the first time, they are able to target the transcription of specific disease-causing genes, conferring unprecedented therapeutic windows to cancer therapy. LeadDiscovery, Dr Chris Berrie and Dr Victoria Richon (Executive Director of Biology, Aton Pharma and HDAC field-leader) have collaborated to produce one of the most comprehensive reviews of HDAC research, pharmaceutical opportunities, and current and future drug development strategies published to date.

The evolution of HDAC research represents a fascinating area of cellular biology, spanning early work demonstrating the role of histone proteins in transcription. As a result of this early work it has become clear that HDACs modulate chromatin plasticity, facilitating protein:DNA interactions and thus transcriptional control. The number of HDAC enzyme subtypes has expanded considerably over the past few years, offering opportunities for the development of HDAC inhibitors with improved specificity. This report overviews the concept of histone remodelling, early HDAC research and the 11 known human class I and class II HDACs, as well as the related sirtuin family. This report also describes the signal transduction pathways, such as phosphorylation, dephosphorylation and SUMOylation, that are able to modulate HDAC activity, a further point of possible therapeutic intervention. One of the particular attractions of HDAC inhibitors is their ability to optimize other therapeutic approaches. HDAC inhibitors are able to increase the efficacy of, for example, retinoic acids, vitamin D analogues and PPAR ligands in cancer models. Given the importance of combination therapy in oncology, this report overviews key aspects of such drug interactions.

Despite the youth of the field of HDAC inhibitors, an impressive body of data describes the ability of these molecules to modulate a wide variety of cellular functions, including cell differentiation, cell cycle progression, apoptosis, cytoskeletal modifications, and angiogenesis. A major aim of the present report was to overview this body of evidence and to demonstrate how this activity translates to therapeutic efficacy in models of cancer. This activity is placed in the context of the cancer market by summarizing the state of development and the market size of the cytostatics, and by identifying companies involved in this field. In addition, drugs in development that inhibit HDACs are identified and profiled; likewise recent patent activity is analyzed.

The most exciting opportunities for HDAC inhibitors are, however, on the horizon. These opportunities are related in part to the requirement of HDACs to complex with other regulatory proteins in order to modulate transcription. Such proteins are numerous, and the nature of the complex determines function. For example, depending on its associated proteins, HDAC1 is involved in the control of thymocyte apoptosis or transcriptional repression in non-Hodgkin lymphoma, and the targeting of specific complexes is therefore likely to confer greater efficacy and specificity than by simply inhibiting selected HDACs. This report identifies well over 100 different complexes and, where possible, attributes cellular function, and therefore represents one of the most up-to-date and complete lists of HDAC functionality. Due to the combinatorial nature of protein:HDAC interaction, this number is set to expand dramatically, and it is quite possible that targeting a selected complex could control the transcription of a single gene. The challenge of the future, therefore, is to attribute specific HDAC complexes to cellular function, and to identify molecules able to block the activity of these functions. Meeting this challenge is likely to produce therapies with efficacy and selectivity not currently possible with existing cytostatics, and an ability to target the expression of selected genes usually reserved for biologics.

Considering the large number of companies involved in the development of cytostatics and the small number with a focus on HDAC inhibitors, development of such molecules will open up collaborative opportunities of a scale rarely seen.

Paralleling the explosion of HDAC research, there has also been an increase in our understanding of the various chemical series that are able to inhibit HDACs and the emergence of a number of tools able to facilitate the screening of both molecular targets and therapeutic candidates. This report describes the chemical series that are associated with HDAC inhibition, including the short-chain fatty acids (eg butyrate), the hyroxamic acids (eg SAHA & Trichostatin), the epoxyketones (eg trapoxin), the benzamides, and a variety of other miscellaneous chemical families. Likewise, this report also overviews recent advances in screening tools, including those able to be miniaturized and adapted for HTS.

In short, this report offers all organizations involved in the developed of cytostatics an unrivaled overview of current research and development activity surrounding HDAC inhibitors and expert strategic input, allowing such organizations to tap into what could be the future of cancer therapy.