What is Histones Deacetylase?

Histones are proteins that bind to the DNA in the nucleus. When histones are bound tightly to the DNA transcription of genes cannot occur. Histone deacetlyases are a class of enyzmes that remove acetyl groups from lysine residues on histone proteins and allow the tighter binding of histone proteins to DNA.

Overview

Epigenetics is the regulation of gene expression and cellular phenotype without a change in the underlying DNA sequence. Histone deacetylases are a class of enzymes that remove acetyl groups from lysine residues allowing tighter interaction between the negatively charged DNA and the histone proteins with positively charged lysine residues. This results in a closed chromatin structure and repression of gene expression. This is one mechanism of epigenetic control.

Acetylation and deacetylation of lysine residues on histones affect DNA compaction, and thus influence transcription of genes or production of mRNA which is then translated into proteins. This is one form of epigenetic regulation where there is a change is gene expression without a change in the underlying DNA sequence.

Histone acetylation results in a repulsion between the negatively charged DNA phosphate backbone and the acetyl groups on the histone proteins, allowing for an open structure of the DNA and gene transcription. Histone Deacetylases (HDACs) by contrast, deacetylate lysine residues allowing tighter interaction between the negatively charged DNA and the histone proteins with positively charged lysine residues. This results in a closed chromatin structure and repression of gene expression.

HDAC’s are grouped into four classes in humans. Classes I, II and IV are Zn2+ dependent enzymes and Class III are Zn2+ independent, NAD-dependent enzymes. Most inhibitors being developed as anti-cancer agents target class I, II and IV HDACs.1

HDAC inhibitors influence gene expression and thus exert control over cell cycle progression, apoptosis and DNA repair. The first HDAC inhibitor was approved by the FDA in 2006 for the treatment of advanced T-cell lymphoma.2

Besides histones there are certain classes of proteins that are a direct substrate for HDAC enzymes. These include HSP90 chaperone protein, p53 tumor suppressor and estrogen receptor-alpha.1

Existing Products

Disease (FDA-approved drug indication) Drug Chemistry Company
Cutaneous T-cell lymphoma Vorinostat (Zolinza) hydroxymate Merck
Cutaneous T-cell lymphoma Romidepsin (Istodax) cyclic tetrapeptide Celgene

HDAC Inhibitors as Non-Neglected Tropical Disease Therapeutics

A number of companies have HDAC inhibitors in various stages of development. Some of these are summarized in the table below.3

Indication Company Phase of Development Notes
Oncology (hepatocellular and colorectal cancers and refractory Hodgkin lymphoma) 4SC Phase II Oral pan-HDAC inhibitor
Oncology Chroma Therapeutics Phase I Targeted HDAC inhibitor
Oncology (Multiple myeloma) Acetylon Pharmaceuticals Phase I Oral HDAC6 inhibitor
Oncology Karus Therapeutics Preclinical Pan HDAC inhibitor
Parkinson’s disease and neurodegenerative orphan indications Envivo Pharmaceuticals Phase I  
CNS (Friedrich’s ataxia) Repligen Preclinical Orally active HDAC inhibitor that crosses blood brain barrier
Inflammation Repligen Preclinical  HDAC6 inhibitor
Inflammation Chroma Therapeutics Lead optimization Targeted HDAC inhibitor to monocyte or macrophage

MethylGene, Pharmacyclics and TopoTarget and Spectrum Pharmaceuticals also have HDAC inhibitors in clinical trials for oncology indications. It is interesting that many of the HDAC inhibitors are orally active which makes therapeutic administration easier.

HDAC inhibitors as Neglected Tropical Disease Therapeutics

There are currently no HDAC inhibitors approved for the treatment of neglected diseases. However, it may be possible to exploit differences between human and neglected disease HDACs to develop selective inhibitors for neglected disease indications. HDAC homologues are present in human infecting parasites causing leishmaniasis, HAT, schistosomiasis and malaria and are being studied as potential drug targets.

References

  1. Khan, O. and La Thangue, N.B. (2012) “HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications.” Immunology and Cell Biology, 90: 85-94
  2. Liszewski K. (2010) “Exploiting HDAC inhibition.” Genetic Engineering and Biotechnology News, Vol. 30, No. 19.
  3. Sannes L.J. (2010) “Epigenetic Drug and Diagnostic Pipelines: DNA methylation, HDAC inhibitors and emerging new targets.” Insight Pharma Report

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Pipline

Analysis

In the area of neglected tropical diseases, HDAC inhibitor development is in the early discovery and target validation stage. There are no HDAC inhibitors in clinical trials for these indications currently.

A large number of HDAC libraries with drug like properties are available as HDACs are being developed by pharma and biotech for cancer and other indications. These libraries can be screened for selectivity to the NTD target. There exists the potential opportunity for repurposing without too much development requirement.

There are also risks involved with this strategy. If the NTD target HDAC homolog and the human HDACs are too similar the inhibitor may have undesirable effects. Also if there are multiple HDACs that can compensate then inhibiting one HDAC alone may not be sufficient to kill the parasite. HDAC inhibitors have to be selected in drug discovery programs to be accessible at the site where the parasite is found.

HDAC homologues in parasites that cause Malaria, HAT and Schistosomiasis1. These are homologous to human HDAC classes I and II.

Parasite HDAC homolog Human HDAC class Characteristics
P. falciparum PfHDAC1 I Expressed in asexual and gametocyte stage
P. falciparum PfHDAC2 II Expressed in asexual and gametocyte stage
P. falciparum PfHDAC3 II Expressed in asexual and gametocyte stage
T. brucei TbDAC1 I Essential in vitro in the blood stream form
T. brucei TbDAC3 II Essential in vitro in the blood stream form
S. mansoni SmHDAC1 I Transcribed in all life cycle stages
S. mansoni SmHDAC3 I Transcribed in all life cycle stages
S. mansoni SmHDAC8 I Transcribed in all life cycle stages

Putative HDACs are also present in L. major, a causative agent for Leishmaniasis. HDAC inhibitors Trichostatin A and to a lesser extent suberoylanilide hydroxamic acid (SAHA) have demonstrated good activity against L. donovani, another species causing Leishmaniasis. However these compounds are also potent inhibitors of human HDACs and will have to be adapted for selectivity to the parasite target.[2]

References

  1. Andrews K.T. et al (2012) “HDAC inhibitors in parasitic diseases” Immunology and Cell Biology, 90: 66-77
  2. von Geldern T. et al (2011) “Kinetoplastid parasites” in Third World Diseases, Topics in Medicinal Chemistry, Editor Richard Elliott, pages 181-242
  3. Acetylon Pharmaceuticals, other disease programs

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Database Resources

HDAC inhibitor database: A small database containing information about molecules or drugs that block HDACs.

The binding database is a public web accessible database of measured binding affinities of protein drug targets with small drug-like molecules. This database contains tens of entries for binding of compounds to HDACs.

Get Involved

To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.