Drug discovery opportunities

Generally, an imbalance between histone methylation and demethylation appears to be correlated with tumorigenesis, and several demethylases are implicated in the pathogenesis of cancer. Both LSD1 and JARID1B are overexpressed in prostate cancer, and LSD1 expression correlates with tumor recurrence during therapy [64]. LSD1 also demethylates p53, repressing p53-mediated transcriptional activation and inhibiting the role of p53 in promoting apoptosis [22]. JARID1B and JMJD2C are over-expressed in breast and testis cancer and esophageal squamous carcinoma [65]. RNAi knockdown of JMJD2C inhibited cell proliferation and highlights this isoform as a potential therapeutic target [16].

A growing body of evidence links demethylase dysfunction to other disease areas. JMJD3 expression is induced in macrophages by the inflammatory transcription factor NFkB in response to microbial stimuli, and 70% of lipopolysaccharide-inducible genes have been shown to be JMJD3 targets [66]. Invading viral pathogens that depend upon the host cell's transcriptional machinery are also subject to the regulatory impact of histone modifications, and this has been specifically demonstrated for LSD1 where depletion or inhibition of its activity with MAOIs resulted in blockade of herpes simplex virus and varicella zoster virus gene expression [67].

While tractability for screening and ligand discovery has been demonstrated for these enzymes, significant challenges remain, notably in identifying chemotypes that show potent and selective inhibition of isoforms of interest while retaining physicochemical properties suitable for the intracellular site of action.

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