The Emerging Therapeutic Potential of Histone Methyltransferase and Demethylase Inhibitors

Abstract

Epigenetics is defined as heritable changes to the transcriptome that are independent of changes in the genome. The biochemical modifications that govern epigenetics are DNA methylation and posttranslational histone modifications. Among the histone modifications, acetylation and deacetylation are well characterized, whereas the fields of histone methylation and especially demethylation are still in their infancy. This is particularly true with regard to drug discovery. There is strong evidence that these modifications play an important role in the maintenance of transcription as well as in the development of certain diseases. This article gives an overview of the mechanisms of action of histone methyltransferases and demethylases, their role in the formation of certain diseases, and available inhibitors. Special emphasis is placed on the strategies that led to the first inhibitors which are currently available and the screening approaches that were used in that process.

The histone demethylase JARID1A is associated with susceptibility to ankylosing spondylitis

“…8 Small molecule inhibitors of both histone methyl transferases and demethylases are now being sought. 19 In this way the balance between the activity of methylating and demethylating enzymes can be manipulated to control gene expression with the possibility of tilting expression levels away from a disease phenotype.…”

A metabolomic approach to identifying platinum resistance in ovarian cancer

“…Targeting the epigenetic status by inhibiting methylation of various genes in tumors is one of the earliest and most pursued chemotherapeutic approaches [59][60][61]. SAM-mediated methylation and polyamine synthesis is being actively investigated in preclinical studies of various cancers [53,62]. Inhibition of GSH activity is also a major area under consideration for specific targeting of chemoresistance [42].…”

Structural insights into transcription complexes

“…CARM1 (also known as PRMT4 (Spannhoff et al, 2009) is a crucial protein involved in many biological processes including the regulation of chromatin structure and transcription via methylation of histones and many transcriptional cofactors. As such, understanding the detailed mechanism of action of this protein at the structural level is important and has implications ranging from pure structural information to potential way of regulating gene expression via inhibitor design (Spannhoff et al, 2009). CARM1 contains 608 amino acids in mouse (and human) is built around a catalytic core domain (residues 150-470 in mouse CARM1) that is well conserved in sequence among all PRMTs members.…”