Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 14, Number 6, 2008


Contents

Histone Deacetylase Inhibitors
Executive Editor: Dimitra Hadjipavlou-Litina


Editorial Pp. 504


Chemical Origins of Isoform Selectivity in Histone Deacetylase Inhibitors Pp. 505-528
K.V. Butler and A.P. Kozikowski
[Abstract]


Isoform-Selective Histone Deacetylase Inhibitors Pp. 529-544
Y. Itoh, T. Suzuki and N. Miyata
[Abstract]


From Natural Products to Small Molecule Ketone Histone Deacetylase Inhibitors: Development of New Class Specific Agents Pp. 545-561
P. Jones and C. Steinkühler
[Abstract]


Inhibitors of NAD⁺ Dependent Histone Deacetylases (Sirtuins) Pp. 562-573
R.C. Neugebauer, W. Sippl and M. Jung
[Abstract]


General Articles


Fibrate-Associated Adverse Effects Beyond Muscle and Liver Toxicity Pp. 574-587
M. Florentin, E.N. Liberopoulos, D.P. Mikhailidis and M.S. Elisaf
[Abstract]


Computational Analysis of the Interaction between Ligan Receptor Pairs Pp. 588-592
Z. Jiang
[Abstract]

Role of Toll-Like Receptors in Immune Responses to Chlamydial Infections Pp. 593-600
A.G. Joyee and Xi Yang
[Abstract]




Abstracts


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Editorial: Histone Deacetylase Inhibitors

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 Steinkühler [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.


Dimitra Hadjipavlou-Litina
Department of Pharmaceutical Chemistry
School of Pharmacy
Aristotle University of Thessaloniki
Thessaloniki 54124
Greece
E-mail:hadjipav@pharm.auth.gr


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Chemical Origins of Isoform Selectivity in Histone Deacetylase Inhibitors
K.V. Butler and A.P. Kozikowski

Histones undergo extensive posttranslational modifications that affect gene expression. Acetylation is a key histone modification that is primarily regulated by two enzymes, one of which is histone deacetylase (HDAC). The activity of HDAC causes transcriptional silencing of DNA. Eleven distinct zinc-dependent histone deacetylase isoforms have been identified in humans. Each isoform has a unique structure and function, and regulates a unique set of genes. HDAC is responsible for the regulation of many genes involved in cancer cell proliferation, and it has been implicated in the pathogenesis of many neurological conditions. HDAC inhibitors are known to be very effective anti-cancer agents, and research has shown them to be potential treatments for many other conditions. Histone deacetylase inhibitors modify the expression of many genes, and it is possible that inhibition of one isoform could cause epigenetic changes that are beneficial to treatment of a disease, while inhibition of another isoform could cause contradictory changes. Selective HDAC inhibitors will be better able to avoid these types of situations than nonspecific inhibitors, and may also be less toxic than pan-HDAC inhibitors. Many potent pan-HDAC inhibitors have already been developed, leaving the development of selective inhibitors at the forefront of HDAC drug development. Certain structural moieties may be added to HDAC inhibitors to give isoform selectivity, and these will be discussed in this review. This review will focus on the applications of selective HDAC inhibitors, inhibitors reported to show selectivity, and the relationship between inhibitor structure and selectivity.


[Back to top]
Isoform-Selective Histone Deacetylase Inhibitors
Y. Itoh, T. Suzuki and N. Miyata

Histone deacetylases (HDACs) catalyze the deacetylation of the acetylated lysine residues of histones and non-histone proteins, and are involved in various fundamental life phenomena, such as gene expression and cell cycle progression. Thus far, eighteen HDAC family members have been identified and they can be divided into two categories, i.e., zinc-dependent enzymes (HDAC1-11) and NAD⁺-dependent enzymes (SIRT1-7). Some of the HDAC isoforms have important roles in cell functions, and are associated with various disease states, including cancer. Therefore, isoform-selective HDAC inhibitors are of great interest, not only as tools for probing the biological functions of the isoforms, but also as candidate therapeutic agents with few side effects. In this review, we cover isoform-selective HDAC inhibitors, including their biochemical and pharmacological functions.


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From Natural Products to Small Molecule Ketone Histone Deacetylase Inhibitors: Development of New Class Specific Agents
P. Jones and C. Steinkühler

Histone deacetylases (HDACs) are one of two counteracting enzyme families whose activity controls the acetylation state of lysine protein residues, notably those contained in the N-terminal extensions of the core histones. Deregulation of the acetylation state of specific lysine residues has been implicated in a multitude of biologic processes, notably cancer, where HDACs are known to be involved in the control of cell cycle progression, cell survival and differentiation. HDAC inhibitors are being developed as anti-neoplastic agents. Nature has led the way in the development of these compounds, with trichostatin A being the first hydroxamic acid HDAC inhibitor identified. Likewise, the disulfide depsipeptide Romidepsin is currently in clinical trials, while an array of cyclic tetrapeptides HDAC inhibitors have been reported. Rational drug design has allowed these cyclic tetrapeptide to be transformed into equally potent small molecule inhibitors selective for either class I or class II HDACs. While acyclic alkyl ketones have been demonstrated to be selective HDAC 1, 2 and 3 inhibitors with efficacy in xenograft models, trifluoromethyl ketones have been shown to be selective inhibitors for class II HDACs and recently have been revealed to bind in the active site of the enzyme in their hydrated form.


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Inhibitors of NAD⁺ Dependent Histone Deacetylases (Sirtuins)
R.C. Neugebauer, W. Sippl and M. Jung

Histone deacetylases (HDACs) are enzymes that deacetylate acetyl lysines in histones and various non-histone proteins. Three classes of histone deacetylases have been described in humans: class I, II and IV were shown to be zinc dependent amidohydrolases and eleven subtypes are known today (HDAC1-11). Class III enzymes depend in their catalysis on NAD⁺ with the subsequent formation of nicotinamide and O acetyl-ADP ribose. 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.

Whereas class I and II HDACs have been identified as valid anticancer targets and clinical studies of their inhibitors as new anticancer agents are under way much less is known about the consequences of class III histone deacetylase inhibition. Sirtuins have been linked to ageing and overexpression of sirtuins leads to a prolonged lifespan in yeast. Lately, sirtuin activity has been tied to the pathogenesis of HIV, cancer and neurodegenerative disease. In the last two years several reports of new sirtuin inhibitors have emerged. Additionally, sirtuin activators have been identified and have been implicated as potential drugs for the ameloriation of metabolic diseases. Thus, the field of sirtuin biology can be investigated with these new tools which will allow in turn to assess the therapeutic potential of those compounds. We will present an overview over sirtuins and their available inhibitors and activators.


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Fibrate-Associated Adverse Effects Beyond Muscle and Liver Toxicity
M. Florentin, E.N. Liberopoulos, D.P. Mikhailidis and M.S. Elisaf

Fibrate derivatives have a 40-year history in the management of dyslipidemia. Although this class of drugs is generally well tolerated, several safety issues have arisen from their use. In the present article we review the literature describing side effects associated with the use of fibrates except for those that are liver and muscle related. These effects are less well known but are clinically relevant.


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Computational Analysis of the Interaction between Ligand-Receptor Pairs
Z. Jiang

Understanding the interactions between protein receptor-ligand pairs is of great pharmaceutical interest for structure-based drug design. It has become apparent that identifying interesting ligand-receptor pairs by computational techniques can offer new insights into functional studies of uncharacterized proteins. More importantly, the matching protein families of ligands and their receptors make it possible more easily to identify the ligands of orphan receptors. Unfortunately, there are few literature reports of the problem of ligand-receptor pairs systematically. In this paper, we will focus on current silico approaches that have been applied for protein ligand-receptor pair prediction. More specifically examples of chemokine receptor-ligand pairs are provided to illustrate the successful application of computational methods for protein ligand-receptor pair research, in particular for current bottlenecks and future directions of this field are discussed finally.


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Role of Toll-Like Receptors in Immune Responses to Chlamydial Infections
A.G. Joyee and Xi Yang

Chlamydiae are important human pathogens which are leading causative agents for a variety of disease conditions including ocular, respiratory and sexually transmitted diseases, thus causing significant morbidity worldwide. Many of the human diseases caused by Chlamydia species are considered to be immunopathologically mediated. Toll like receptors (TLRs) have emerged as one of the major components of the immune system. Recognition of pathogen associated molecular patterns (PAMPs) by TLRs results in the activation of signaling events that induce the expression of effector molecules such as cytokines and chemokines which control the activation of adaptive immune responses. The precise immune mechanisms involved in resistance or pathogenesis to chlamydial infection, especially in the TLR signaling and downstream events during the innate phase of infection initiating the adaptive immune responses remains largely unknown. This review focuses on elaborating the current knowledge on the role of TLRs in immune responses to chlamydial infection. Although chlamydial components like lipopolysaccharide (LPS) and chlamydial heat shock protein 60 (cHSP60) are recognized by TLR4, the intact organisms stimulates the innate immune cells through TLR2, which also plays an important role as a PRR for Chlamydia. While the individual role of different TLRs such as TLR2, TLR4 and TLR9 in chlamydial infection is becoming delineated, studies have demonstrated the essential role of the TLR adapter molecule MyD88 in the generation of immune responses to Chlamydia infection. Given that there is no effective vaccine available for Chlamydia till date, a better understanding of the immunological and molecular mechanisms mediated by TLRs will greatly aid in possibly exploiting these molecules as immunotherapeutic targets.