Histone demethylase inhibitors

In an effort to avoid inhibiting the demethylases with 20G competitors, we recently described the inhibition of the JMJD2 histone demethylases by ejection of the structural Zn(II) ion by known Zn-ejecting compounds such as dis-ulfiram and ebselen. " This strategy presents a means of achieving selectivity for a particular demethylase family by targeting a non-active site part of the protein. It is possible that similar approaches may be useful in the development of demethylase inhibitors with chnical relevance. 

Figure 5.13 Histone demethylases. Structures and mechanisms are illustrated for the two subclasses of histone lysine demethylases. (a) Views from an X-ray crystal structure of LSDl (PDB ID 2V1D) in complex with cofactor FAD and a peptide substrate analogue, where methionine replaces methylated lysine, and outline mechanism of the LSDl-catalysed demethylation reaction, (b) Views from an X-ray crystal structure of JMJD2A (PDB ID 20Q6) in complex with co-factor analogue N-oxa-lylglycine and histone substrate trimethylated at H3K9 (note that Ni(II) replaces Fe(II) for crystallography), and outline mechanism of JmjC-domain catalysed lysine demethylation. (c) Representative inhibitors of LSDl and JmjC-domain demethylases.

Lohse B, Kristensen JL, Kristensen LH, Agger K, Helin K, Gajhede M, Clausen RP (2011) Inhibitors of histone demethylases. Bioorg Med Chem 19 3625-3636 Cho WC (2012) Exploiting the therapeutic potential of microRNAs in human cancer. Expert Opin Ther Targets 16 345-350... 

---