Histone deacetylase inhibitor
Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that
HDIs have a long history of use in psychiatry and neurology as
Cellular biochemistry/pharmacology
To carry out gene expression, a cell must control the coiling and uncoiling of DNA around
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.[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 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.[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 known human histone deacetylases as of 2015 were classified into four groups (I-IV):[11]
- Class I, which includes are related to yeast RPD3 gene;
- Class IIA, which includes are related to yeast Hda1 gene;
- Class III, also known as the sirtuinsare 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 2005, some examples in decreasing order of the typical zinc binding affinity were:[12]
- hydroxamic acids (or hydroxamates), such as trichostatin A,
- cyclic tetrapeptides (such as trapoxin B), and the depsipeptides,
- benzamides,
- electrophilic ketones, and
- the valproic acid.
Asd of 2007, "second-generation" HDIs included the hydroxamic acids vorinostat (SAHA), belinostat (PXD101), resminostat, abexinostat, Givinostat, LAQ824, and panobinostat (LBH589); and the benzamides : entinostat (MS-275), tacedinaline (CI994), zabadinostat, and mocetinostat (MGCD0103).[13][14]
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.[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:
Uses
Psychiatry and neurology
HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. The prime example of this is
Enhancement of memory formation was increased in mice given vorinostat, or by genetic knockout of the HDAC2 gene in mice.[19] While that may have relevance to Alzheimer's disease, it was shown that some cognitive deficits were restored in actual transgenic mice with a model of Alzheimer's disease (3xTg-AD) by orally administered nicotinamide, a competitive HDI of Class III sirtuins.[20]Preclinical research for the treatment of depression
2012 research into the causes of
Effects on gene expression
As of 2011 various HDIs have been studied for their connection to the regulation of mood and behavior, each having different, specific effects on the regulation of various genes. The most commonly studied genes include
Effects on depressive behaviors
Pre-clinical research on the use of HDIs to treat depression use rodents to model human depression. The
Cancer treatment
Pan-HDAC inhibitors have shown anticancer potential in several in in vitro and in vivo studies, focused on Pancreatic, Esophageal squamous cell carcinoma (ESCC), Multiple myeloma, Prostate carcinoma, Gastric cancer, Leukemia, breast, Liver cancer, ovarian cancer, non-Hodgkin lymphoma and Neuroblastoma.[24] Because of the massive effect of pan-HDAC inhibition, witnessed by the very low dosage concentration used and by the countless biological functions affected, many scientists have focused their attention on combining the less specific HDACi treatment with other more specific anti-cancer drugs, such as the efficacy of the combination treatment with the pan-HDAC inhibitor LBH589 (panobinostat) and the BET bromodomain JQ1 compound.[25]
Inflammatory diseases
Trichostatin A (TSA) and others are being investigated as anti-inflammatory agents.[26]
HIV/AIDS
One study noted the use of panobinostat, entinostat, romidepsin, and vorinostat specifically for the purpose of reactivating latent HIV in order to diminish the reservoirs. Vorinostat was noted as the least potent of the HDAC inhibitors in this trial.[27] Another study found that romidepsin led to a higher and more sustained level of cell-associated HIV RNA reactivation than vorinostat in latently infected T-cells in vitro and ex vivo.[28]
Other diseases
Myocardial Infarction
As of 2008, HDIs were also being studied as protection of heart muscle in
References
- PMID 14613312.
- PMID 20536416.
- PMID 19914074.
- PMID 15708534.
- S2CID 26722842.
- PMID 10922406.
- ^ PMID 17951399.
- PMID 24512308.
- PMID 23786452.
- PMID 15032670.
- ^ "Histone deacetylase (HDAC) Inhibitors Database". hdacis.com. Retrieved 6 October 2015.
- ^ PMID 15822187.
- PMID 17455259.
- S2CID 1439957.
- PMID 15681027.
- PMID 17694074.
- S2CID 40126163.
- S2CID 14344174.
- PMID 19424149.
- PMID 18987186.
- ^ S2CID 39241791.
- ^ PMID 25818247.
- ^ PMID 20961400.
- PMID 32429325.
- PMID 26733615.
- PMID 17325655.
- PMID 25393648.
- PMID 24722454.
- ^ Commissioner, Office of the (March 26, 2024). "FDA Approves Nonsteroidal Treatment for Duchenne Muscular Dystrophy". FDA.
- PMID 18606865.
External links
- HK application 1124320, Maier, Thomas; Beckers, Thomas; Hummel, Rolf-Peter; Feth, Martin; Müller, Matthias; Bär, Thomas; Volz, Jürgen, "Novel Sulphonylpyrroles as Inhibitors of Hdac S Novel Sulphonylpyrroles", published October 22, 2009
- HDAC inhibitors base information about molecules that block HDACs.
- Tambunan US, Wulandari EK (2010). "Identification of a better Homo sapiens Class II HDAC inhibitor through binding energy calculations and descriptor analysis". BMC Bioinformatics. 11 (Suppl 7): S16. PMID 21106123.