Lien DOI – 10.1016/B978-0-12-816422-8.00005-2
Histone methyltransferases are potential therapeutic targets for human diseases, in particular cancer. Among them, DOT1L is a lysine histone methyltransferase (KHMT) that catalyzes the methylation of lysine 79 on histone 3. Structurally, its catalytic domain is distinguished by the presence of a seven-stranded β-sheet motif, common to arginine histone methyltransferases, making it a unique KHMT. In addition to this unicity, which makes it a very interesting therapeutic target from a medicinal chemistry point of view, DOT1L plays a major role in mixed-lineage rearranged leukemia, an important subset of acute leukemia with very poor overall survival rate. Here, after an introduction to DOT1L and its role in MLL-r leukemia, we discuss the development of DOT1L inhibitors for the treatment of MLL-r and the assays used to discover and evaluate the inhibitors.