Methyltransferase enzymes are promising epigenetic oncotargets. Recent efforts toward the development of inhibitors of two methyltransferases, EZH2 and G9a, as potential anticancer therapies are reviewed with a focus on the structure-activity relationships of compounds published from 2012. Benzamide-substituted 2-pyridones are still by far the most popular selective EZH2 inhibitor class but alternative classes are now being reported. There are now three EZH2 inhibitors in clinical development with the first responses in lymphoma patients with tazemetostat. Potent inhibitors of G9a are also published but no examples have yet reached the clinic. Dual blockage of EZH2-G9a is exemplified by one series of compounds. We conclude this review by presenting the three clinical stage compounds with the first clinical response data.
Keywords: 2-pyridones; EZH2; G9a inhibitors; HKMT; SET domain; dual inhibitors; enhancer of zeste homolog 2; epigenetics; inhibitors; oncology; tazemetostat.