Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach

Misdirected catalytic activity of Histone Methyltransferase Dot1L is believed to be causative for a subset of highly aggressive acute leukemias. Targeting the catalytic domain of DOT1L represents a potential therapeutic approach for these leukemias. In the context of a comprehensive DOT1L hit finding strategy, a knowledge-based virtual screen of the DOT1L SAM binding pocket led to the discovery of 2, a non-nucleoside fragment mimicking key interactions of SAM bound to DOT1L. Fragment linking of 2 and 3, an induced back pocket binder identified in earlier studies, followed by careful ligand optimization led to the identification of 7, a highly potent, selective and structurally novel DOT1L Inhibitor.