Docking of a small-molecule inhibitor into the active site of the human DNMT1 enzyme. The catalytic cysteine residue is indicated in yellow, other amino acids important for the positioning of the inhibitor are shown in mangenta. | © dkfz.de

Hypermethylation of tumor suppressor genes and other cancer-related genes has been been shown to be closely associated with cellular transformation. The resulting changes in the epigenetic modification patterns have been termed “epimutations“. In contrast to classical genetic mutations, epimutations are principally reversible. This reversion can be facilitated by the pharmacological inhibition of DNA methyltransferases. Thus, DNA methyltransferase inhibitors open novel possibilities in the treatment of cancer. We are using various approaches to characterize the modes of action of the established DNA methyltransferase inhibitors azacytidine and decitabine in the laboratory and in the clinic. We are also working towards the development of novel small molecules with specific inhibitory activity towards human DNA methyltransferases. We have established biochemical assays for high-throughput compound screening and cellular assays for the characterization and further development of hits.