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

ACS Med Chem Lett. 2017 Feb 14;8(3):338-343. doi: 10.1021/acsmedchemlett.6b00519. eCollection 2017 Mar 9.


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.

Keywords: Dot1L; fragment linking; inhibitor; mixed lineage leukemia; protein lysine methyltransferase.