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Histone deacetylase inhibitor

Histone deacetylase inhibitors (HDAC inhibitors, HDIs) are a class of compounds that interfere with the function of histone deacetylase.

HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. More recently they are being investigated as possible treatments for cancers,[1][2] parasitic[3] and inflammatory diseases.[4]

Cellular biochemistry/pharmacology

To carry out gene expression, a cell must control the coiling and uncoiling of DNA around histones. This is accomplished with the assistance of histone acetyl transferases (HAT), which acetylate the lysine residues in core histones leading to a less compact and more transcriptionally active chromatin, and, on the converse, the actions of histone deacetylases (HDAC), which remove the acetyl groups from the lysine residues leading to the formation of a condensed and transcriptionally silenced chromatin. Reversible modification of the terminal tails of core histones constitutes the major epigenetic mechanism for remodeling higher-order chromatin structure and controlling gene expression. HDAC inhibitors (HDI) block this action and can result in hyperacetylation of histones, thereby affecting gene expression.[5][6][7]

The histone deacetylase inhibitors are a new class of cytostatic agents that inhibit the proliferation of tumor cells in culture and in vivo by inducing cell cycle arrest, differentiation and/or apoptosis. Histone deacetylase inhibitors exert their anti-tumour effects via the induction of expression changes of oncogenes or tumour suppressor, through modulating that the acetylation/deactylation of histones and/or non-histone proteins such as transcription factors.[8] Histone acetylation and deacetylation play important roles in the modulation of chromatin topology and the regulation of gene transcription. Histone deacetylase inhibition induces the accumulation of hyperacetylated nucleosome core histones in most regions of chromatin but affects the expression of only a small subset of genes, leading to transcriptional activation of some genes, but repression of an equal or larger number of other genes. Non-histone proteins such as transcription factors are also targets for acetylation with varying functional effects. Acetylation enhances the activity of some transcription factors such as the tumor suppressor p53 and the erythroid differentiation factor GATA-1 but may repress transcriptional activity of others including T cell factor and the co-activator ACTR. Recent studies [...] have shown that the estrogen receptor alpha (ERalpha) can be hyperacetylated in response to histone deacetylase inhibition, suppressing ligand sensitivity and regulating transcriptional activation by histone deacetylase inhibitors.[9] Conservation of the acetylated ER-alpha motif in other nuclear receptors suggests that acetylation may play an important regulatory role in diverse nuclear receptor signaling functions. A number of structurally diverse histone deacetylase inhibitors have shown potent antitumor efficacy with little toxicity in vivo in animal models. Several compounds are currently in early phase clinical development as potential treatments for solid and hematological cancers both as monotherapy and in combination with cytotoxics and differentiation agents."[10]

HDAC classification

Based on their homology of accessory domains to yeast histone deacetylases, the 18 currently known human histone deacetylases are classified into four groups (I-IV):[11]

  • Class I, which includes HDAC1, -2, -3 and -8 are related to yeast RPD3 gene;
  • Class II, which includes HDAC4, -5, -6, -7, -9 and -10 are related to yeast Hda1 gene;
  • Class III, also known as the sirtuins are related to the Sir2 gene and include SIRT1-7
  • Class IV, which contains only HDAC11 has features of both Class I and II.

HDI classification

The “classical” HDIs act exclusively on Class I and Class II HDACs by binding to the zinc-containing catalytic domain of the HDACs. These classical HDIs fall into several groupings, in order of decreasing potency:[12]

  1. hydroxamic acids (or hydroxamates), such as trichostatin A,
  2. cyclic tetrapeptides (such as trapoxin B), and the depsipeptides,
  3. benzamides,
  4. electrophilic ketones, and
  5. the aliphatic acid compounds such as phenylbutyrate and valproic acid.

"Second-generation" HDIs include the hydroxamic acids vorinostat (SAHA), belinostat (PXD101), LAQ824, and panobinostat (LBH589); and the benzamides : entinostat (MS-275), CI994, and mocetinostat (MGCD0103).[13][14]

The sirtuin Class III HDACs are dependent on NAD+ and are, therefore, inhibited by nicotinamide, as well derivatives of NAD, dihydrocoumarin, naphthopyranone, and 2-hydroxynaphaldehydes.[15]

Additional functions

HDIs should not be considered to act solely as enzyme inhibitors of HDACs. A large variety of nonhistone transcription factors and transcriptional co-regulators are known to be modified by acetylation. HDIs can alter the degree of acetylation nonhistone effector molecules and, therefore, increase or repress the transcription of genes by this mechanism. Examples include: ACTR, cMyb, E2F1, EKLF, FEN 1, GATA, HNF-4, HSP90, Ku70, NF-κB, PCNA, p53, RB, Runx, SF1 Sp3, STAT, TFIIE, TCF, YY1, etc.[12][16]


Psychiatry and neurology

HDIs have a long history of use in psychiatry and neurology as mood stabilzers and anti-epileptics. The prime example of this is valproic acid, marketed as a drug under the trade names Depakene, Depakote, and Divalproex. In more recent times, HDIs are being studied as a mitigator for neurodegenerative diseases such as Alzheimer's disease and Huntington's disease.[17] Enhancement of memory formation is increased in mice given the HDIs sodium butyrate or SAHA, or by genetic knockout of the HDAC2 gene in mice.[18] While that may have relevance to Alzheimer's disease, it was shown that some cognitive deficits were restored in actual transgenic mice that have a model of Alzheimer's disease (3xTg-AD) by orally administered nicotinamide, a competitive HDI of Class III sirtuins.[19]

Cancer treatment

Also in recent years, there has been an effort to develop HDIs as a cancer treatment or adjunct[20][21] The exact mechanisms by which the compounds may work are unclear, but epigenetic pathways are proposed.[10][22][23] HDAC inhibitors can induce p21 (WAF1) expression, a regulator of p53's tumor suppressor activity. HDACs are involved in the pathway by which the retinoblastoma protein (pRb) suppresses cell proliferation.[24] The pRb protein is part of a complex that attracts HDACs to the chromatin so that it will deacetylate histones.[25] HDAC1 negatively regulates the cardiovascular transcription factor Kruppel-like factor 5 through direct interaction.[26] Estrogen is well-established as a mitogenic factor implicated in the tumorigenesis and progression of breast cancer via its binding to the estrogen receptor alpha (ERα). Recent data indicate that chromatin inactivation mediated by HDAC and DNA methylation is a critical component of ERα silencing in human breast cancer cells.[27]


Clinical trials

Started phase III clinical trials

Started pivotal phase II clinical trials

Started phase II clinical trials

Started phase I clinical trials


Inflammatory diseases

Trichostatin A (TSA) and others are being investigated as anti-inflammatory agents.[51]


After the successful initial round of in vitro research in January 2013, the Danish Research Council awarded the research team lead by Dr. Ole Søgaard from the Danish Aarhus University Hospital the amount of $2 million to proceed with clinical trials on 15 humans. The HDAC inhibitors flush HIV from the reservoirs it builds within the DNA of infected cells. After that a separate vaccination to eliminate HIV allows the immune system to neutralize the virus.[52]

Other diseases

HDIs are also being studied as protection of heart muscle in acute myocardial infarction.[53]


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