Inhibitors of both the N-methyl lysyl- and arginyl- demethylase activities of the JmjC oxygenases

摘要

The Jumonji C (JmjC) family of 2-oxoglutarate (2OG) dependent oxygenases have established roles in theregulation of transcription via the catalysis of demethylation of Nε-methylated lysine residues in histone tails,especially the N-terminal tail of histone H3. Most human JmjC KDMs are complex enzymes, with ‘readerdomains’ in addition to their catalytic domains. Recent biochemical evidence has shown that some, but not all,JmjC KDMs also have Nω-methyl arginyl demethylase (RDM) activity. JmjC KDM activity has been linked tomultiple cancers and some JmjC proteins are therapeutic targets. It is therefore important to test not onlywhether compounds in development inhibit the KDM activity of targeted JmjC demethylases, but alsowhether they inhibit other activities of these proteins. Here we report biochemical studies on the potentialdual inhibition of JmjC KDM and RDM activities using a model JmjC demethylase, KDM4E (JMJD2E). Theresults reveal that all of tested compounds inhibit both the KDM and RDM activities, raising questions aboutthe in vivo effects of the inhibitors.