Histone deacetylase inhibitor
Encyclopedia
Histone deacetylase inhibitors (HDAC inhibitors, HDI) 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 stabilzers and anti-epileptics. More recently they are being investigated as possible treatments for cancers and inflammatory diseases.
(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.
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 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. Conservation of the acetylated ERalpha 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."
histone deacetylases, the 18 currently known human histone deacetylases are classified into four groups (I-IV):
"Second-generation" HDIs include the hydroxamic acids vorinostat
(SAHA), belinostat (PXD101), LAQ824, and panobinostat
(LBH589); and the benzamide
s : entinostat
(MS-275), CI994, and mocetinostat (MGCD0103).
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.
, EKLF
, FEN 1, GATA
, HNF-4, HSP90
, Ku70, NF-κB, PCNA
, p53, RB
, Runx, SF1 Sp3, STAT
, TFIIE, TCF, YY1
, etc.
, 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
.
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.
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.
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. The pRb protein is part of a complex that attracts HDACs to the chromatin
so that it will deacetylate histones. HDAC1 negatively regulates the cardiovascular transcription factor Kruppel-like factor 5 through direct interaction. 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.
Started pivotal phase II clinical trials
Started phase II clinical trials
Started phase I clinical trials
(TSA) and others are being investigated as anti-inflammatory agents.
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
of histone deacetylase
Histone deacetylase
Histone deacetylases are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone...
.
HDIs have a long history of use in psychiatry and neurology as mood stabilzers and anti-epileptics. More recently they are being investigated as possible treatments for cancers 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 acetylasesHistone acetyltransferase
Histone acetyltransferases are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl CoA to form ε-N-acetyl lysine....
(HAT), which acetylate the lysine residues in core histones leading to a less compact and more transcriptionally active chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
, 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
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
. HDAC inhibitors (HDI) block this action and can result in hyperacetylation of histones, thereby affecting gene expression.
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 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. Conservation of the acetylated ERalpha 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 yeastYeast
Yeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...
histone deacetylases, the 18 currently known human histone deacetylases are classified into four groups (I-IV):
- Class I, which includes HDAC1HDAC1Histone deacetylase 1 is an enzyme that in humans is encoded by the HDAC1 gene.-Interactions:HDAC1 has been shown to interact with RAD9A, DNMT3L, MTA1, FKBP3, CDC20, CDH1, Host cell factor C1, BUB3, Nuclear receptor co-repressor 2, IKZF1, Prohibitin, EVI1, DDX5, DNMT3A, Mothers against...
, -2, -3HDAC3Histone deacetylase 3 is an enzyme that in humans is encoded by the HDAC3 gene.-Interactions:HDAC3 has been shown to interact with HDAC9, HDAC7A, Retinoblastoma protein, RBBP4, Testicular receptor 2, MAP3K7IP2, Peroxisome proliferator-activated receptor delta, GTF2I, Histone deacetylase 5, RELA,...
and -8HDAC8Histone deacetylase 8 is an enzyme that in humans is encoded by the HDAC8 gene, and is biologically involved in skull morphogenesis and metabolic control of the ERR-alpha/PGC1-alpha transcriptional complex. -Further reading:- External links :...
are related to yeast RPD3 gene; - Class II, which includes HDAC4HDAC4Histone deacetylase 4, also known as HDAC4, is a protein which in humans is encoded by the HDAC4 gene.- Function :Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects...
, -5, -6HDAC6Histone deacetylase 6 is an enzyme that in humans is encoded by the HDAC6 gene.-Interactions:HDAC6 has been shown to interact with HDAC11 and Zinc finger and BTB domain-containing protein 16.-Further reading: -External links:...
, -7, -9HDAC9Histone deacetylase 9 is an enzyme that in humans is encoded by the HDAC9 gene.-Interactions:HDAC9 has been shown to interact with SIN3A, Nuclear receptor co-repressor 1, CBX5, HDAC3, Myocyte-specific enhancer factor 2A and SUV39H1....
and -10HDAC3Histone deacetylase 3 is an enzyme that in humans is encoded by the HDAC3 gene.-Interactions:HDAC3 has been shown to interact with HDAC9, HDAC7A, Retinoblastoma protein, RBBP4, Testicular receptor 2, MAP3K7IP2, Peroxisome proliferator-activated receptor delta, GTF2I, Histone deacetylase 5, RELA,...
are related to yeast Hda1 gene; - Class III, also known as the sirtuins are related to the Sir2 gene and include SIRT1-7, and
- Class IV, which contains only HDAC11HDAC11Histone deacetylase 11 is a histone deacetylase enzyme that in humans is encoded by the HDAC11 gene.It is the only Class IV HDAC....
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:- hydroxamic acidHydroxamic acidA hydroxamic acid is a class of chemical compounds sharing the same functional group in which an hydroxylamine is inserted into a carboxylic acid. Its general structure is R-CO-NH-OH, with an R as an organic residue, a CO as a carbonyl group, and a hydroxylamine as NH2-OH. They are used as metal...
s (or hydroxamates), such as trichostatin ATrichostatin ATrichostatin A is an organic compound that serves as an antifungal antibiotic and selectively inhibits the class I and II mammalian histone deacetylase families of enzymes, but not class III HDACs . TSA inhibits the eukaryotic cell cycle during the beginning of the growth stage...
, - cyclic tetrapeptides (such as trapoxin B), and the depsipeptideDepsipeptideA depsipeptide is a peptide in which one or more of the amide bonds are replaced by ester bonds.Depsipeptides have often been used in research to probe the importance of hydrogen bond networks in protein folding kinetics and thermodynamics. They are also found in nature as natural products...
s, - benzamideBenzamideBenzamide is an off-white solid with the chemical formula of C6H5CONH2. It is a derivative of benzoic acid. It is slightly soluble in water, and soluble in many organic solvents.- External links :* *...
s, - electrophilic ketoneKetoneIn organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
s, and - the aliphatic acid compounds such as phenylbutyrateSodium phenylbutyrateSodium phenylbutyrate is an orphan drug, marketed by Ucyclyd Pharma under the trade name Buphenyl and by Swedish Orphan International as Ammonaps.It has been used to treat urea cycle disorders....
and valproic acidValproic acidValproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
.
"Second-generation" HDIs include the hydroxamic acids vorinostat
Vorinostat
Vorinostat or suberoylanilide hydroxamic acid is a member of a larger class of compounds that inhibit histone deacetylases...
(SAHA), belinostat (PXD101), LAQ824, and panobinostat
Panobinostat
Panobinostat is an experimental drug developed by Novartis for the treatment of various cancers. It is a hydroxamic acid and acts as a non-selective HDAC inhibitor.-Clinical trials:...
(LBH589); and the benzamide
Benzamide
Benzamide is an off-white solid with the chemical formula of C6H5CONH2. It is a derivative of benzoic acid. It is slightly soluble in water, and soluble in many organic solvents.- External links :* *...
s : entinostat
Entinostat
Entinostat, also known as SNDX-275 and MS-275, is a benzamide histone deacetylase inhibitor undergoing clinical trials for treatment of various cancers.Entinostat inhibits class I HDAC1 and HDAC3 with IC50 of 0.51 μM and 1.7 μM, respectively....
(MS-275), CI994, and mocetinostat (MGCD0103).
The sirtuin Class III HDACs are dependent on NAD+ and are, therefore, inhibited by nicotinamide
Nicotinamide
Nicotinamide, also known as niacinamide and nicotinic acid amide, is the amide of nicotinic acid . Nicotinamide is a water-soluble vitamin and is part of the vitamin B group...
, as well derivatives of NAD, dihydrocoumarin, naphthopyranone, and 2-hydroxynaphaldehydes.
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, E2F1E2F1
Transcription factor E2F1 is a protein that in humans is encoded by the E2F1 gene.-Interactions:E2F1 has been shown to interact with NCOA6, Retinoblastoma-like protein 1, Retinoblastoma protein, GTF2H1, SKP2, PURA, NPDC1, Sp2 transcription factor, Sp1 transcription factor, CUL1, ARID3A, TOPBP1,...
, EKLF
EKLF
Erythroid Krüppel-like Factor is a transcription factor that is necessary for the proper maturation of erythroid cells. The molecule has two domains; the transactivation domain and the chromatin-remodeling domain. The carboxyl terminal is composed of three C2H2 zinc fingers that binds to DNA,...
, FEN 1, GATA
GATA transcription factor
GATA transcription factors are a family of transcription factors characterized by their ability to bind to the DNA sequence "GATA".-Genes:* GATA1 * GATA2 * GATA3 * GATA4 * GATA5 * GATA6...
, HNF-4, HSP90
Hsp90
Hsp90 is a molecular chaperone and is one of the most abundant proteins expressed in cells. It is a member of the heat shock protein family, which is upregulated in response to stress...
, Ku70, NF-κB, PCNA
PCNA
Proliferating Cell Nuclear Antigen, commonly known as PCNA, is a protein that acts as a processivity factor for DNA polymerase δ in eukaryotic cells. It achieves this processivity by encircling the DNA, thus creating a topological link to the genome...
, p53, RB
Retinoblastoma protein
The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in the majority types of cancer. One highly studied function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide...
, Runx, SF1 Sp3, STAT
STAT protein
The STAT protein regulates many aspects of growth, survival and differentiation in cells...
, TFIIE, TCF, YY1
YY1
Transcriptional repressor protein YY1 is a protein that in humans is encoded by the YY1 gene.-Interactions:YY1 has been shown to interact with Histone deacetylase 2, FKBP3, ATF6, Myc, SAP30, EP300, HDAC3, NOTCH1 and RYBP....
, etc.
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 acidValproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
, 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
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
and Huntington's disease
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
.
Enhancement of memory formation is increased in mice given the HDIs sodium butyrate
Sodium butyrate
Sodium butyrate is a compound with formula Na. It is the sodium salt of butyric acid. It has various effects on cultured mammalian cells including inhibition of proliferation, induction of differentiation and induction or repression of gene expression. As such, it can be used in lab to bring about...
or SAHA
Vorinostat
Vorinostat or suberoylanilide hydroxamic acid is a member of a larger class of compounds that inhibit histone deacetylases...
, or by genetic knockout of the HDAC2 gene in mice.
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.
Cancer treatment
Also in recent years, there has been an effort to develop HDIs as a cancer treatment or adjunct The exact mechanisms by which the compounds may work are unclear, but epigenetic pathways are proposed.HDAC inhibitors can induce p21
P21
p21 / WAF1 also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1 is a protein that in humans is encoded by the CDKN1A gene located on chromosome 6 .- Function :...
(WAF1) expression, a regulator of p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
's tumor suppressor
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
activity. HDACs are involved in the pathway by which the retinoblastoma protein
Retinoblastoma protein
The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in the majority types of cancer. One highly studied function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide...
(pRb) suppresses cell proliferation. The pRb protein is part of a complex that attracts HDACs to the chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
so that it will deacetylate histones. HDAC1 negatively regulates the cardiovascular transcription factor Kruppel-like factor 5 through direct interaction. Estrogen is well-established as a mitogenic factor implicated in the tumorigenesis and progression of breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
via its binding to the estrogen receptor alpha
Estrogen receptor alpha
Estrogen receptor alpha , also known as NR3A1 , is a nuclear receptor that is activated by the sex hormone estrogen...
(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.
Approved
- VorinostatVorinostatVorinostat or suberoylanilide hydroxamic acid is a member of a larger class of compounds that inhibit histone deacetylases...
was licenced by the U.S. FDA in October 2006 for the treatment of cutaneous T cell lymphomaCutaneous T Cell lymphomaCutaneous T cell lymphoma is a class of non-Hodgkin's lymphoma, which is a type of cancer of the immune system. Unlike most non-Hodgkin's lymphomas , CTCL is caused by a mutation of T cells. The malignant T cells in the body initially migrate to the skin, causing various lesions to appear...
(CTCL). - RomidepsinRomidepsinRomidepsin , codenamed FK228 and FR901228, is an anticancer agent undergoing clinical trials as a treatment for cutaneous T-cell lymphoma , peripheral T-cell lymphoma, and a variety of other cancers...
(trade name Istodax) was licenced by the US FDA in Nov 2009 for cutaneous T-cell lymphoma (CTCL),
Clinical trials
Started phase III clinical trials- PanobinostatPanobinostatPanobinostat is an experimental drug developed by Novartis for the treatment of various cancers. It is a hydroxamic acid and acts as a non-selective HDAC inhibitor.-Clinical trials:...
(LBH589) is in clinical trials for various cancers including a phase III trial for cutaneous T cell lymphoma (CTCL). - Valproic acidValproic acidValproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
(as Mg valproate) in phase III trials for cervical cancerCervical cancerCervical cancer is malignant neoplasm of the cervix uteri or cervical area. One of the most common symptoms is abnormal vaginal bleeding, but in some cases there may be no obvious symptoms until the cancer is in its advanced stages...
and ovarian cancerOvarian cancerOvarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
.
Started pivotal phase II clinical trials
- Belinostat (PXD101) has had a phase II trial for relapsed ovarian cancerOvarian cancerOvarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
, and reported good results for T cell lymphoma.
Started phase II clinical trials
- Mocetinostat (MGCD0103) is undergoing clinical trials for treatment of various cancers (including follicular lymphomaFollicular lymphomaFollicular lymphoma is the most common of the indolent non-Hodgkin's lymphomas, and the second most common form of non-Hodgkin's lymphomas overall. It is defined as a lymphoma of follicle center B-cells , which has at least a partially follicular pattern...
, Hodgkin lymphoma and acute myeloid leukemiaAcute myeloid leukemiaAcute myeloid leukemia , also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute...
). - PCI-24781 has started a phase II trial for sarcomaSarcomaA sarcoma is a cancer that arises from transformed cells in one of a number of tissues that develop from embryonic mesoderm. Thus, sarcomas include tumors of bone, cartilage, fat, muscle, vascular, and hematopoietic tissues...
, and another for lymphomaLymphomaLymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage... - EntinostatEntinostatEntinostat, also known as SNDX-275 and MS-275, is a benzamide histone deacetylase inhibitor undergoing clinical trials for treatment of various cancers.Entinostat inhibits class I HDAC1 and HDAC3 with IC50 of 0.51 μM and 1.7 μM, respectively....
(MS-275) in phase II for Hodgkin lymphoma, lung cancerLung cancerLung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
and breast cancerBreast cancerBreast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
. - SB939 starting a phase II trial for Recurrent or Metastatic Prostate CancerProstate cancerProstate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
(HRPC). (phase I results, Phase II results for myelofibrosisMyelofibrosisMyelofibrosis, also known as myeloid metaplasia, chronic idiopathic myelofibrosis, osteomyelofibrosis and primary myelofibrosis is a disorder of the bone marrow...
) - Resminostat (4SC-201) an oral pan-HDACi. Results re Hodgkin lymphoma Also in trials for hepatocellular carcinomaHepatocellular carcinomaHepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...
for which it has FDA Orphan DrugOrphan drugAn orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease...
status. - GivinostatGivinostatGivinostat or gavinostat is a histone deacetylase inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities...
(ITF2357) for refractory leukemias and myelomas.
Started phase I clinical trials
- CUDC-101 intended for cancer, has started clinical trials, it also inhibits EGFREpidermal growth factor receptorThe epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
and HER2. Early results reported in Nov 2010. - AR-42 has started clinical trials in 2010 for various cancers (relapsed or treatment-resistant multiple myelomaMultiple myelomaMultiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
, chronic lymphocytic leukemiaChronic lymphocytic leukemiaB-cell chronic lymphocytic leukemia , also known as chronic lymphoid leukemia , is the most common type of leukemia. Leukemias are cancers of the white blood cells . CLL affects B cell lymphocytes. B cells originate in the bone marrow, develop in the lymph nodes, and normally fight infection by...
or lymphomaLymphomaLymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
). The trial should report in 2013 - CHR-2845, CHR-3996
- 4SC-202 selective, for advanced hematological indications
- Also sulforaphaneSulforaphaneSulforaphane is an organosulfur compound that exhibits anticancer, antidiabetic, and antimicrobial properties in experimental models. It is obtained from cruciferous vegetables such as broccoli, Brussels sprouts or cabbages. The enzyme myrosinase transforms glucoraphanin, a glucosinolate, into...
Inflammatory diseases
Trichostatin ATrichostatin A
Trichostatin A is an organic compound that serves as an antifungal antibiotic and selectively inhibits the class I and II mammalian histone deacetylase families of enzymes, but not class III HDACs . TSA inhibits the eukaryotic cell cycle during the beginning of the growth stage...
(TSA) and others are being investigated as anti-inflammatory agents.
Other diseases
- GivinostatGivinostatGivinostat or gavinostat is a histone deacetylase inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities...
(ITF2357) is also under investigation for treatment of polycythemia veraPolycythemia veraPolycythemia vera is a blood disorder in which the bone marrow makes too many red blood cells. It may also result in the overproduction of white blood cells and platelets. Most of the health concerns associated with polycythemia vera are caused by the blood being thicker as a result of the...
(PV), essential thrombocythemia (ET) and myelofibrosisMyelofibrosisMyelofibrosis, also known as myeloid metaplasia, chronic idiopathic myelofibrosis, osteomyelofibrosis and primary myelofibrosis is a disorder of the bone marrow...
(MF).