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Epigenetics
Bioactive Small Molecules for Epigenetics ResearchEpigenetic modification of chromatin includes methylation of genomic DNA as well as post-translational modification of chromatin-associated proteins, mainly histones. Cell-permeable small-molecule modulators have become a valuable tool in the investigation of gene and protein functions. The use of small molecules to modulate cellular and in vivo systems is receiving strong interest among researchers in academia as well as pharma. The discovery of small molecule regulators (activators or inhibitors) of epigenetic modification enzymes provides researchers with pharmacological tools with which to investigate the biological consequences of chromatin modifications. The major classes of inhibitors/modulators are classified based on their activity and use. DNA Methyltransferase Inhibitors DNA Methyltransferase Inhibitors DNA methyltransferases are a family of enzymes that catalyze the transfer of methyl group to DNA. There are five related DNA cytosine- 5-methyltransferases (DNMTs) that transfer a methyl group from S-adenosylmethionine (AdoMet, SAM) to the C-5 position of cytosine. Inhibitors have been shown to have anti-proliferative activity. They can reactivate the expression of genes that have been repressed by DNA methylation. Nucleoside analog inhibitors:
Non-nucleoside analog inhibitors:
Histone Methylation Histone methyltransferases (HMTs), histone-lysine N-methyltransferase and histone-arginine N-methyltransferase, are enzymes which catalyzye the transfer of one to three methyl groups from the cofactor S-Adenosyl methionine to lysine and arginine residues of histone proteins. Histone Lysine Methyltransferase (HKMT) inhibitors
Histone Lysine Demethylase inhibitors:
Protein Arginine Methyltransferase (PRMT) modulators:
Histone Deacetylases Histone deacetylases (HDACs) are enzymes that remove acetyl groups from lysines of histones and a number of other regulatory and structural proteins. They play critical roles in chromatin remodeling and are involved in transcription regulation, cell-cycle progression, cell survival and differentiation. So far, 18 HDACs have been identified and divided into 3 distinct enzyme classes. Class I and II HDACs are zinc dependent. Class I, homologous to yeast Rpd3, includes HDAC1, 2, 3, and 8. Class II (HDAC4, 5, 6, 7, 9, 10) resembles yeast Hda1. Class I and II HDACs are associated with malignant transformations and are targets for cancer drugs. Inhibitors of Class I and II HDACs are largely classified into four groups on the basis of their chemical structures. Short-chain fatty acid inhibitors
Hydroxamic acid inhibitors:
Benzamide inhibitors
Cyclic tetrapeptide and natural product inhibitors:
Other HDAC inhibitors:
Histone Acetyltransferases (HAT) Histone acetyltransferases (HAT) 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. Histone acetylation is generally linked to transcriptional activation. These are generally associated with euchromatin. HAT inhibitors:
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