CHAPTER 6: Targeting Histone Lysine Methyltransferases in Cancer

Post-translational modifications of histones are recognised as important determinants of chromatin architecture and are well appreciated as an instrument to exert control over cellular processes that require access to DNA such as transcription, replication and DNA repair. Among the covalent histone modifications, histone lysine methylation has received increasing attention in the field of oncology. Cancer genomic sequencing campaigns have provided evidence that alterations in histone lysine methylation networks occur frequently in cancer, raising interest in the relevant enzymes responsible for adding and removing them (methyltransferases and demethylases) as potential oncology targets. Many successful drug discovery campaigns executed over recent years have led to high-quality histone lysine methyltransferase inhibitors with remarkable potency and selectivity. These compounds elicit selective cancer cell killing in vitro and robust efficacy in vivo, suggesting that targeting histone lysine methylation pathways may be a useful strategy for cancer treatment. This chapter reviews the relevant histone lysine methyltransferase targets and currently available small molecule inhibitors.