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

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 acetylases (HAT) which acetylate the lysine residues in core histones leading to a less compact and more transcriptionally active chromatin, and conversely 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, therefore affecting gene expression. ^[1]

HDAC classification

HDACs are classified in four groups based on their homology to yeast histone deacetylases:

• 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, and
• 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^[2]:

1. hydroxamic acids, 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 (MS275), CI994, and mocetinostat (MGCD0103).^[3][4]

The sirtuin Class III HDACs are NAD+ dependent and are therefore inhibited by nicotinamide, as well derivatives of NAD, dihydrocoumarin, naphthopyranone, and 2-hydroxynaphaldehydes.^[5]

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 thereby increase or repress the transcription of genes by this mechanism. Examples include: ACTR, cMyb, E2F1, EKLF, FEN 1, GATA, HNF-4, HSP90, Ku70, NFκB, PCNA, p53, RB, Runx, SF1 Sp3, STAT, TFIIE, TCF, YY1, etc. ^[2][6]

Uses

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. More recently, HDIs are being studied as a mitigator for neurodegenerative diseases such as Alzheimer's disease and Huntington's disease.^[7] 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.^[8] 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.^[9]

Cancer treatment

Also in recent years, there has been an effort to develop HDIs as a cancer treatment or adjunct^{[10] [11]} The exact mechanisms by which the compounds may work are unclear, but epigenetic pathways are proposed.^[12] Richon et al. found that 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.^[13] The pRb protein is part of a complex which attracts HDACs to the chromatin so that it will deacetylate histones.^[14] HDAC1 negatively regulates the cardiovascular transcription factor Kruppel-like factor 5 through direct interaction.^[15] 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.^[16]

• Vorinostat was licenced by the U.S. FDA in October 2006 for the treatment of cutaneous T cell lymphoma (CTCL).
• Romidepsin (trade name Istodax) was licenced by the US FDA in Nov 2009 for cutaneous T-cell lymphoma (CTCL),
• Panobinostat is under investigation for various cancers including cutaneous T cell lymphoma (CTCL).
• Valproic acid is under investigation for various cancers including leukemia.
• Mocetinostat (MGCD0103) is undergoing clinical trials for treatment of various cancers (including follicular lymphoma, Hodgkin lymphoma and acute myeloid leukemia).

Other diseases

• ITF2357 is under investigation for treatment of polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF).^[17]

References

External links

• US Patent "Novel Sulphonylpyrroles as Inhibitors of Hdac "