Post-translational chromatin modifications play a key role in the regulation of gene expression. Aberrant modification of histone lysine methylation state and the subsequent global or local change in chromatin structure is a characteristic of many cancers. There are 5 members of the KDM4-subfamily of Jumonji C histone demethylases. They primarily catalyse the demethylation of histone substrates H3K9Me3 and H3K36Me3 to the corresponding di- or mono-methyl products, in an Fe(II)-dependent mechanism which utilises 2-oxoglutarate (2-OG) as a co-substrate. A number of structurally diverse small-molecule inhibitors of KDM4 enzymes have been reported, however the majority of these compounds are 2-OG competitive and inhibit other KDM histone demethylases, in particular the KDM5 subfamily. We chose to pursue histone peptide substrate competitive inhibitors, which do not compete with the 2-OG co-substrate for KDM4 inhibition. We hypothesised that that this approach could be advantageous in providing compounds displaying selectivity for KDM4 subfamily inhibition over other KDMs including the KDM5-subfamily. Our strategy was to design and synthesise novel H3K9Me3 methyllysine mimetics for incorporation into short histone H3 substrate 8-mer peptide sequences to transform the substrate peptide into an inhibitor. We will present a series of novel amino acids, informed by structure-based and in silico design to be effective H3K9Me3 methyllysine mimics. These were combined into substrate peptide backbones in order to modify the substrate peptide into a series of KDM4-subfamily inhibitors. Initial investigations into replacement of K9Me3 with natural amino acids afforded an 8-mer peptide exhibiting selective inhibition of KDM4 over KDM5. We will also report the synthesis, biochemical potency and protein-ligand structural characterisation of these H3K9Me3 histone substrate-mimetic inhibitors versus KDM4A.

Peptidomimetic inhibitors of the KDM4-subfamily of histone lysine demethylases: Transitioning from substrate to inhibitor

255th National Meeting (2018)

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