JMJD2 oxygenases, recently identified as a possible anti-cancer targets, catalyze the demethylation of Ne-lysyl methylation on histone tails. Most JMJD2 inhibitors developed to date chelate the active site Fe(II) and also compete with 2OG, a common cofactor for all dioxygenases, making selective inhibition of JMJD2 oxygenases difficult to achieve. Structures of JMJD2A revealed a Cys3-His Zn(II) binding site close to the Ne-methyl lysine-residue binding site, not present in dioxygenases outside the JMJD2 subfamily. We reasoned that the catalytic activity of the JMJD2 histone demethylases might be inhibited by compounds known to act as Zn(II) ejectors from proteins. Using assays for catalytic activity, Zn(II) release and protein stabilization, we have demonstrated Zn(II) ejection as a novel approach for selective inhibition of the JMJD2 histone demethylases. Such selective mechanisms of inhibition may prove useful in probing the complexity of epigenetic modifications and the regulatory enzymes that catalyze them.

Zn-ejection for the selective inhibition of JMJD2 histone demethylases

243rd National Meeting (2012)

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