ヒストン脱アセチル化酵素阻害薬、ヒストン脱アセチル化酵素阻害剤、ヒストンデアセチラーゼ阻害薬、ヒストンデアセチラーゼ阻害剤

関: HDACI

WordNet

limit, block, or decrease the action or function of; "inhibit the action of the enzyme"; "inhibit the rate of a chemical reaction"
control and refrain from showing; of emotions, desires, impulses, or behavior (同)bottle up, suppress
limit the range or extent of; "Contact between the young was inhibited by strict social customs"
a substance that retards or stops an activity
a simple protein containing mainly basic amino acids; present in cell nuclei in association with nucleic acids

PrepTutorEJDIC

〈感情・欲望・行動・作用など〉‘を'抑制する / (…しないように)〈人〉‘を'抑制する,妨げる《+『名』+『from』+『名』(do『ing』)》
抑制する人(物) / 化学反応抑制剤

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/10/06 09:51:12」(JST)

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Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that inhibit 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]

1 Cellular biochemistry/pharmacology
- 1.1 HDAC classification
- 1.2 HDI classification
- 1.3 Additional functions
2 Uses
- 2.1 Psychiatry and neurology
  - 2.1.1 Pre Clinical Research - HDI therapy for the treatment of depression
    - 2.1.1.1 Effects on gene expression
    - 2.1.1.2 Effects on depressive behaviors
- 2.2 Cancer treatment
  - 2.2.1 Approved
  - 2.2.2 Phase 3 and phase 2 clinical trials
  - 2.2.3 Phase I Clinical trials
- 2.3 Inflammatory diseases
- 2.4 HIV/AIDS
- 2.5 Other diseases
3 References
4 External links

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 open chromatin resulting from inhibition of histone deacetylases can result in either the up-regulation or the repression of genes.^[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 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). Some examples in decreasing order of the typical zinc binding affinity:^[12]

hydroxamic acids (or hydroxamates), such as trichostatin A,
cyclic tetrapeptides (such as trapoxin B), and the depsipeptides,
benzamides,
electrophilic ketones, and
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 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: 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.^[12]^[16]^[17]

Uses

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.^[18] Enhancement of memory formation is 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 that have a model of Alzheimer's disease (3xTg-AD) by orally administered nicotinamide, a competitive HDI of Class III sirtuins.^[20]

Pre Clinical Research - HDI therapy for the treatment of depression

Recent research into the causes of depression has highlighted some possible gene-environment interactions that could explain why after much research, no specific genes or loci which would indicate risk for depression have emerged.^[21] Recent studies estimate that even after successive treatments with multiple antidepressants, almost 35% of patients did not achieve remission,^[22] suggesting that there could be an epigenetic component to depression that is not being addressed by current pharmacological treatments. Environmental stressors, namely traumatic stress in childhood such as maternal deprivation and early childhood abuse have been studied for their connection to a high risk of depression in adulthood. In animal models, these types of trauma have been shown to have significant effects on histone acetylation, particularly at gene loci which have known connection to behavior and mood regulation.^[21]^[23] Current research has focused on the use of HDI therapy for depression after studies on depressed patients in the middle of a depressive episode found increased expression of HDAC2 and HDAC5 mRNA compared to controls and patients in remission.^[23]

Effects on gene expression

Various HDAC inhibitors (HDI) 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 Brain-derived neurotrophic factor (BDNF) and Glial cell line-derived neurotrophic factor (GDNF) both of which help regulate neuron growth and health, whose down regulation can be a symptom of depression.^[23] Multiple studies have shown that treatment with an HDI helps to up regulate expression of BDNF: valproic acid (commonly used to treat epilepsy and bipolar disorder)^[22] as well as sodium butyrate^[23] both increased expression of BDNF in animal models of depression. One study which traced GDNF levels in the ventral striatum found increased gene expression upon treatment with SAHA.^[22]

Effects on depressive behaviors

Pre-clinical research on the use of HDAC inhibitors (HDI) for the treatment of depression use rodents to model human depression. The tail suspension test (TST) and the forced swimming test (FST) measure the level of defeat in rodents— usually after treatment with chronic stress— which mirrors symptoms of human depression. Alongside tests for levels of HDAC mRNA, acetylation and gene expression these behavioral tests are compared to controls to determine whether or not treatment with an HDI has been successful in ameliorating symptoms of depression. Studies which used SAHA or MS-275 as their treatment compound found treated animals displayed gene expression profiles similar to those treated with fluoxetine, and displayed similar anti-depressant like behavior.^[21]^[22]^[23] Sodium butyrate is commonly used as a candidate for mood disorder treatment: studies using it both alone and in co-treatment with fluoxetine report subjects with increased performance on both TST and FST^[22] in addition to increased expression of BDNF.^[23]

Cancer treatment

Also in recent years, there has been an effort to develop HDIs as a cancer treatment or adjunct.^[24]^[25] The exact mechanisms by which the compounds may work are unclear, but epigenetic pathways are proposed.^[10]^[26]^[27] 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.^[28] The pRb protein is part of a complex that attracts HDACs to the chromatin so that it will deacetylate histones.^[29] HDAC1 negatively regulates the cardiovascular transcription factor Kruppel-like factor 5 through direct interaction.^[30] 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.^[31]

Approved

Vorinostat was licensed by the U.S. FDA in October 2006 for the treatment of cutaneous T cell lymphoma (CTCL).
Romidepsin (trade name Istodax) was licensed by the US FDA in Nov 2009 for cutaneous T-cell lymphoma (CTCL).
Chidamide approved by China in 2015 for peripheral T-cell lymphoma (PTCL).
Panobinostat (trade name Farydak) was licensed by the US FDA in Feb 2015 for the treatment of multiple myeloma.^[32]
Belinostat (PXD101) has had a phase II trial for relapsed ovarian cancer, and in 2009 reported good results for T cell lymphoma. Approved July 2014 in the US for the use against peripheral T-cell lymphoma.^[33]

Phase 3 and phase 2 clinical trials

Started phase III clinical trials

Panobinostat (LBH589) is in clinical trials for various cancers including a phase III trial for cutaneous T cell lymphoma (CTCL).
Valproic acid (as Mg valproate) As of 2011^[update] due to have completed phase III trials for cervical cancer^[34] and ovarian cancer.^[35] Has also been trialled in spinal muscular atrophy.^{[citation needed]}

Started pivotal phase II clinical trials

none since 2014 ?

Started phase II clinical trials

Mocetinostat (MGCD0103) is undergoing clinical trials for treatment of various cancers (including follicular lymphoma, Hodgkin lymphoma and acute myeloid leukemia).
Abexinostat (PCI-24781) has started a phase II trial for sarcoma,^[36] and another for lymphoma^[37]
Entinostat (MS-275) in phase II for Hodgkin lymphoma, lung cancer and breast cancer.^[38]
SB939 starting a phase II trial for Recurrent or Metastatic Prostate Cancer (HRPC).^[39] (phase I results,^[40])
Resminostat (4SC-201) an oral pan-HDACi. Results re Hodgkin lymphoma^[41] Also in trials for hepatocellular carcinoma^[42] for which it has FDA Orphan Drug status,^[43] and met phase II primary endpoint.^[44]
Givinostat (ITF2357)^[38] for refractory leukemias and myelomas.
Quisinostat (JNJ-26481585)

Phase I Clinical trials

Started phase I clinical trials

HBI-8000, (a benzamide HDI), inhibits Class I HDAC1, HDAC2, HDAC3, as well as Class IIb HDAC10^[45] Approved in China (for peripheral T-cell lymphoma (PTCL)) and having Orphan drug status in Japan.^[46]
Kevetrin, selective for HDAC2.^[47] Is past the 10th cohort in an Open-Label Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic study in patients with advanced solid tumors.^[48] Early good results reported for Ovarian Cancer Spleen Metastasis Jan 20 2015^[49]
CUDC-101 intended for cancer, has started clinical trials,^[50] it also inhibits EGFR and HER2. Early results reported in Nov 2010.^[51] Results publishes in 2014.^[52]
AR-42^[53] has started clinical trials in 2010 for various cancers (relapsed or treatment-resistant multiple myeloma, chronic lymphocytic leukemia or lymphoma).^[54] The trial should report in 2013^[55] In 2012 AR-42 got 2 Orphan Drug designations from the FDA for two benign tumour types.^[56]
CHR-2845, CHR-3996^[57]
4SC-202 selective, for advanced hematological indications^[42]
CG200745 for solid tumors.^[58]
ACY-1215, selective for HDAC6, in two clinical trials for multiple myeloma in combination with bortezomib (Velcade, Takeda Millennium) and with lenalidomide (Revlimid, Celgene).^[59]
ME-344, for solid refractory tumors^[60]
Also sulforaphane^[61]^[62]

Preclinical

Inflammatory diseases

Trichostatin A (TSA) and others are being investigated as anti-inflammatory agents.^[63]

HIV/AIDS

After the successful initial round of in vitro research in January 2013, the Danish Research Council awarded the research team led by Dr. Ole Søgaard from the Danish Aarhus University Hospital the amount of $2 million to proceed with clinical trials on 15 humans. The goal is for HDAC inhibitors to flush HIV from the reservoirs it builds within the DNA of infected cells, followed by a vaccination to help the immune system to neutralize any replicating virus.^[64]

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.^[65] 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.^[66]

Other diseases

Givinostat (ITF2357) is also under investigation for treatment of polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF).

HDIs are also being studied as protection of heart muscle in acute myocardial infarction.^[67]

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^ Adcock IM (April 2007). "HDAC inhibitors as anti-inflammatory agents". British Journal of Pharmacology. 150 (7): 829–31. PMC 2013887 . PMID 17325655. doi:10.1038/sj.bjp.0707166.
^ Gayomali, Chris (April 29, 2013). "Breakthrough: Is an HIV cure just a few months away?". The Week. The Week Publications. Retrieved September 12, 2013.
^ Elliott JH, Wightman F, Solomon A, Ghneim K, Ahlers J, Cameron MJ, Smith MZ, Spelman T, McMahon J, Velayudham P, Brown G, Roney J, Watson J, Prince MH, Hoy JF, Chomont N, Fromentin R, Procopio FA, Zeidan J, Palmer S, Odevall L, Johnstone RW, Martin BP, Sinclair E, Deeks SG, Hazuda DJ, Cameron PU, Sékaly RP, Lewin SR (2014). "Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy". PLoS Pathogens. 10 (11): e1004473. PMC 4231123 . PMID 25393648. doi:10.1371/journal.ppat.1004473.
^ Wei DG, Chiang V, Fyne E, Balakrishnan M, Barnes T, Graupe M, Hesselgesser J, Irrinki A, Murry JP, Stepan G, Stray KM, Tsai A, Yu H, Spindler J, Kearney M, Spina CA, McMahon D, Lalezari J, Sloan D, Mellors J, Geleziunas R, Cihlar T (April 2014). "Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing". PLoS Pathogens. 10 (4): e1004071. PMC 3983056 . PMID 24722454. doi:10.1371/journal.ppat.1004071.
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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. PMC 2957684 . PMID 21106123. doi:10.1186/1471-2105-11-S7-S16.

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English Journal

PU.1 and epigenetic signals modulate 1,25-dihydroxyvitamin D and C/EBPα regulation of the human cathelicidin antimicrobial peptide gene in lung epithelial cells.

Wei R, Dhawan P, Baiocchi RA, Kim KY, Christakos S.
Journal of cellular physiology. 2019 Jul;234(7)10345-10359.
LL-37, the only known human cathelicidin which is encoded by the human antimicrobial peptide (CAMP) gene, plays a critical role in protection against bacterial infection. We previously demonstrated that cathelicidin is induced by 1,25-dihydroxyvitamin D (1,25(OH) D ) in human airway epithelial cel
PMID 30387140

Anti-metastatic activity of MPT0G211, a novel HDAC6 inhibitor, in human breast cancer cells in vitro and in vivo.

Hsieh YL, Tu HJ, Pan SL, Liou JP, Yang CR.
Biochimica et biophysica acta. Molecular cell research. 2019 Jun;1866(6)992-1003.
Triple-negative breast cancer (TNBC) is associated with an increased risk of metastasis and a poor prognosis. The invasive ability of TNBC relies on actin reorganization and is regulated by histone deacetylase 6 (HDAC6). The present study aimed to examine the effect of MPT0G211, a novel HDAC6 inhibi
PMID 30867138

Identification of ortho-hydroxy anilide as a novel scaffold for lysine demethylase 5 inhibitors.

Jaikhan P, Buranrat B, Itoh Y, Chotitumnavee J, Kurohara T, Suzuki T.
Bioorganic & medicinal chemistry letters. 2019 May;29(10)1173-1176.
Fe(II)/α-ketoglutarate-dependent lysine demethylases (KDMs) are attractive drug targets for several diseases including cancer. In this study, we designed and screened ortho-substituted anilides that are expected to function as Fe(II) chelators, and identified ortho-hydroxy anilide as a novel scaffo
PMID 30928196

Japanese Journal

Enhanced transgene expression by plasmid-specific recruitment of histone acetyltransferase

Journal of bioscience and bioengineering 123(3), 277-280, 2017-03
NAID 40021152720

呼吸器感染症の病態におけるエピジェネティクスの意義

呼吸器内科 = Respiratory medicine 31(2), 176-183, 2017-02
NAID 40021117568

Different Schedule-dependent Effects of Epigenetic Modifiers on Cytotoxicity by Anticancer Drugs in Colorectal Cancer Cells

Ｂｉｏｌｏｇｉｃａｌ　＆　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｂｕｌｌｅｔｉｎ, 2017
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リンク元	「ヒストンデアセチラーゼ阻害剤」「ヒストンデアセチラーゼ阻害薬」「ヒストン脱アセチル化酵素阻害剤」「ヒストン脱アセチル化酵素阻害薬」「HDACI」
関連記事	「inhibit」「inhibitor」「histo」「deacetylase」