Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that inhibit histone deacetylases. Since deacetylation of histones produces transcriptionally silenced heterochromatin, HDIs can render chromatin more transcriptionally active and induce epigenomic changes. HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics, such as valproic acid. Since at least 2003 they have been investigated as possible treatments for cancers, parasitic and inflammatory diseases.
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 euchromatin, 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. The open chromatin resulting from inhibition of histone deacetylases can result in either the up-regulation or the repression of genes. As of 2015, the histone deacetylase inhibitors were 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 suppressors through modulating the acetylation/deacetylation of histones and/or non-histone proteins such as transcription factors. 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 GATA1 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. 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."
HDAC classification Based on their homology of accessory domains to yeast histone deacetylases, the 18 known human histone deacetylases as of 2015 were classified into four groups (I-IV):
Class I, which includes HDAC1, -2, -3 and -8 are related to yeast RPD3 gene; Class IIA, which includes HDAC4, -5, -7 and -9; Class IIB -6, 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, II and Class IV HDACs by binding to the zinc-containing catalytic domain of the HDACs. These classical HDIs can be classified into several groupings named according to the chemical moiety that binds to the zinc ion (except cyclic tetrapeptides which bind to the zinc ion with a thiol group). As of 2025, some examples in decreasing order of the typical zinc binding affinity were: 1. hydroxamic acids (or hydroxamates), such as trichostatin A. As of 2025, "second-generation" HDIs includes the hydroxamic acids : vorinostat (SAHA), belinostat (PXD101), resminostat, abexinostat, givinostat, LAQ824, ivaltinostat, nanatinostat and panobinostat (LBH589), tinostamustine, domatinostat, fimepinostat/(CUDC-907), CUDC-101. 2. cyclic tetrapeptides (such as trapoxin B), and the depsipeptides such as: romidepsin, bocodepsin hydrochloride. 3. benzamides : entinostat (MS-275), tacedinaline (CI994), zabadinostat, and mocetinostat (MGCD0103). 4. electrophilic ketones, and the aliphatic acid compounds such as sodium phenylbutyrate and valproic acid. The sirtuin/Class III HDACs are dependent on NAD+ and are, therefore, inhibited by nicotinamide, as well as derivatives of NAD, dihydrocoumarin, naphthopyranone, and 2-hydroxynaphthaldehydes. γ-Aminobutyric acid (GABA) might also act as an HDAC inhibitor similarly to structurally related compounds like butyrate (butyric acid), β-hydroxybutyrate (BHB), and valproic acid (valproate), though findings are mixed.
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, MKP-1, NF-κB, PCNA, p53, RB, Runx, SF1 Sp3, STAT, TFIIE, TCF, YY1, etc.
Uses
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