Moebitz, Henrik, Machauer, Rainer, Holzer, Philipp, Vaupel, Andrea, Stauffer, Frederic, Ragot, Christian, Caravatti, Giorgio, Scheufler, Clemens, Hommel, Ulrich, Tiedt, Ralph, Beyer, Kim, Chen, Chao, Zhu, Hugh and Gaul, Christoph (2017) Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach. ACS Medicinal Chemistry Letters, 8 (3). pp. 338-343. ISSN 19485875

Abstract

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.

Item Type:	Article
Keywords:	Dot1L fragment linking inhibitor mixed lineage leukemia protein lysine methyltransferase
Date Deposited:	31 Mar 2017 00:45
Last Modified:	25 Jan 2019 00:45
URI:	https://oak.novartis.com/id/eprint/32137