Abstract

The chemical decoration of the nucleosome through covalent modification lies at the heart of epigenetic regulation. Among the various structural alterations, methylation occupies a special position as it occurs in both DNA and histone proteins. This chapter summarizes the chemistry and biology of the first discovered protein demethylases, the lysine‐specific demethylases (LSDs). Typically, strong noncovalent interactions embed the FAD cofactor within the active site as in LSDs, whereas monoamine oxidases (MAOs) feature a covalent linkage to the protein. Among the epigenetic proteins, LSD1 has advanced from bench to bedside in the remarkably short space of a decade. Nine LSD1 inhibitors are currently in clinical development. Though the evidence for LSD1 as a target is most compelling in acute myeloid leukemia and small cell lung cancer, other cancers and non‐cancer indications are under investigation. The current emphasis is on LSD1; future investigations will undoubtedly shed light on the physiological role of the isoform LSD2.