The epigenetic component of cancer is now well-established and epigenetic therapeutics targeting histone deacetylase and DNA methyltransferase enzymes have received FDA approval. Histone lysine methyltransferases (HKMTs) are a new and promising epigenetic target class for cancer treatment, but the search for HKMT inhibitors is still in its infancy. First, chaetocin, a fungal metabolite belonging to the 3,6 epidithio-diketopiperazine (ETP) class, was previously described as a specific inhibitor of the HKMT SU(VAR)3 9. Like other ETP molecules however, it exhibits a broad cytotoxicity due to the presence of the disulfide bridge. The requirement of this moiety for HKMT inhibition has been questioned. We reasoned that access to semi-synthetic analogues devoid of such functionality would provide valuable insight into its reported HKMT inhibitory activity. Our results revealed a total loss in inhibitory potency upon modification of the disulfide bridge. In addition, we conducted biochemical and mass spectroscopy studies on the mechanism of action of chaetocin. Our results demonstrated the ETP functionality of chaetocin to be responsible for its reported HKMT inhibitory activity and suggest that chaetocin is a non-specific inhibitor. The stereochemical course of ETP desulfurisation by triphenylphosphine has also been investigated by comparison of experimental and computationally simulated chiroptical spectra. Our data showed that all ETPs are desulfurised with retention of stereochemistry. Second, BIX-01294 has been identified as an inhibitor of G9a/GLP HKMTs. In light of the expected structural similarities of EZH2's peptide binding site with that of G9a, we felt we could use this molecule as a starting point for the reversal of H3K27-mediated gene silencing. We anticipated that upon derivatisation of BIX 01294, it might be possible to expand the biological activities of the parent compound and gain EZH2 inhibitory activity. A library of analogues has been prepared in collaboration with co-workers in the Fuchter group and has been assessed in biological assays. Three compounds have been identified in a cell-based assay to lead to re-expression of EZH2 target genes and their biological activities have been further assessed.