Abstract
Altered chromatin structures and dynamics are responsible for a range of human malignancies, among which the status of histone lysine methylation remains of paramount importance. Histone lysine methylation is maintained by the relative activities of sequence-specific methyltransferase (KMT) writers and demethylase (KDM) erasers, with aberrant enzymatic activities or expression profiles closely correlated with multiple human diseases. Hence, targeting these epigenetic enzymes should provide a promising avenue for pharmacological intervention of aberrantly marked sites within the epigenome. Here we present an up-to-date critical evaluation on the development and optimization of potent small molecule inhibitors targeted to histone KMTs and KDMs, with the emphasis on contributions of structural biology to development of epigenetic drugs for therapeutic intervention. We anticipate that ongoing advances in the development of epigenetic inhibitors should lead to novel drugs that site-specifically target KMTs and KDMs, key enzymes responsible for maintenance of the lysine methylation landscape in the epigenome.