Drugs Modifying The Epigenetic Status

Several chemical entities that affect the DNA methylation landscape of the genome are now being used.

• The earliest of these, 5-azacytidine and azacytidine, are chemical analogs of the nucleoside cytidine and its deoxy derivative, decitabine. Through incorporation into DNA (during replication) and RNA (during transcription), they inhibit methyltransferases and thereby cause demethylation of the sequence. Their lack of specificity, has also been deemed to potentiate the carcinogenic process, given the impending effect on genomic stability.
• Zebularine is a cytidine analog that inhibits DNA methylation;
• MG98, an antisense oligonucleotide targets the 3′-untranslated region of the maintenance methyltransferase DNMT1, thereby inhibiting it.
• RG108 effectively blocks DNMTs, particularly DNMT1, and inhibits their activity.
• Psammaplins, a natural product derived from the sea sponge Pseudoceratina purpurea inhibits DNMTs as well as histone deacetylases.

Increasing work is being carried out in developing drugs that affect histone modifications.

• Histone deacetylase inhibitors have been objects of attention in anticancer drug development as they are seen as presenting a potential strategy to reverse aberrant epigenetic changes associated with cancer