Editorial [ Histone Deacetylase Inhibitors Executive Editor: Dimitra Hadjipavlou-Litina ]

Histone deacetylases (HDACs) are a family of enzymes that regulate chromatin remodeling and gene transcription. They consequently control critical cellular processes, including cell growth, cell cycle regulation, DNA repair, differentiation, proliferation, and apoptosis. Histone deacetylases are known to play an important role in the regulation of gene expression by catalyzing the deacetylation of the acetylated e-amino groups of specific histone lysine residues. The post-translational acetylation status of chromatin, which regulates chromatin structure, is determined by the competing activities of two classes of enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs).HATs function to acetylate N-terminal lysine residues in nuclear histones, resulting in the neutralization of the positive charges on the histones and a more open, transcriptionally active chromatin structure, while HDACs function to deacetylate and suppress transcription. Therefore, HDACs have emerged as an attractive target for the development of new anticancer drugs. A variety of natural and synthetic compounds have been reported that show HDAC inhibitory activity and antitumor effects. HDAC inhibitors such as trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), and Trapoxin B (TPX B) have been reported to inhibit cell growth, induce terminal differentiation in tumor cells, and prevent the formation of tumors in mice. A number of structurally diverse HDAC inhibitors have been reported and most of them belong to hydroxamic acid derivatives, typified by TSA and SAHA, which can interact with zinc in the active site. Some of these inhibitors are currently in phase I/II clinical trials. All the above facts prompted us to deal with HDACs in a thematic issue, as a biomolecule target for “new leads” in the modulation of cellular processes, including cell growth, cell cycle regulation, DNA repair, differentiation, proliferation, and apoptosis inflammation processes. In their review Kozikowski and Butler [1] highlight the methods used to design and to synthesize HDAC inhibitors (HDACIs) that have proven to be particularly interesting either as research tools or even as drugs, due to their ability to act as potent pan-selective HDAC inhibitors, or to their ability to exhibit desirable degrees of isoform selectivity. As will be apparent, the HDACIs contain different zinc binding groups (ZBGs), which can contribute to isoform selectivity as well as potential side effects. Efforts will be made to summarize structural features that may be most relevant to achieve isoform selectivity, as such inhibitors are most needed in order to improve our understanding of HDAC biology. The review will be focused on the HDAC structural features and their small molecule inhibitors that may lead to the design of superior isoform selective HDACIs. Yukihiro Itoh, Takayoshi Suzuki and Naoki Miyata [2] will present isoform selective HDAC inhibitors and their biochemical and pharmacological functions. Since now, eighteen HDAC family members have been identified and they are divided into two categories, i.e., zinc-dependent enzymes (HDAC1-11) and NAD+-dependent enzymes (SIRT1-7). Some of the HDAC isoforms have been reported to play important roles in cell functions and be associated with the proliferation of cancer cells. Therefore, isoform selective HDAC inhibitors are of great interest not only as tools for probing the biological functions of the isoform but also as anticancer agents with few side effects. It is hotly debated in the literature whether class specific, or indeed isoform selective, HDACi may represent second generation therapeutic agents. Most of the HDACi's belong to two structural classes, either hydroxamic acids or aminobenzamides. A third class of HDACi are represented by the natural products Apicidin and Trapoxin, containing a long alkyl ketone, which is believed to reach down into the active site of the enzyme. Jones and Steinkuhler [3], in their review will focus on the related natural products and the development of these structural complex molecules into small molecule HDACi's. . Methods to identify class II HDACi's will be discussed, including a novel method to identify HDAC 4, 5, 6 and 7 inhibitors. In the last months an entirely novel series of class II selective HDACi's has been reported in the patent literature and initial data on these compounds will be disclosed in this article. Based on the homology to the yeast histone deacetylase Sir2p, the NAD+-dependent deacetylases have been termed sirtuins and seven members (Sirt1-7) have been described in humans. Sirtuins have been linked to aging and overexpression of sirtuins leads to a prolonged lifespan in yeast. Lately, sirtuins activity has been tied to the pathogenesis of HIV and cancer. Additionally, in the last two years several report on new sirtuin inhibitors have emerged. Thus, Neugebauer and Jung [4], are reviewing the field of sirtuin biology, investigating these new tools which will allow in turn to assess the therapeutic potential of their available inhibitors. References [1] Butler KV, Kozikowski AP.Chemical Origins of Isoform Selectivity in Histone Deacetylase Inhibitors. Curr Pharm Des 2008; 14(6): 505-528. [2] Itoh Y, Suzuki T, Miyata N. Isoform-Selective Histone Deacetylase Inhibitors. Curr Pharm Des 2008; 14(6): 529-544. [3] Jones P, Steinkühler C. From Natural Products to Small Molecule Ketone Histone Deacetylase Inhibitors: Development of New Class Specific Agents. Curr Pharm Des 2008; 14(6): 545-561. [4] Neugebauer RC, Sippl W, Jung M. Inhibitors of NAD+ Dependent Histone Deacetylases (Sirtuins). Curr Pharm Des 2008; 14(6): 562- 573.