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

Moebitz, Henrik and Machauer, Rainer and Holzer, Philipp and Vaupel, Andrea and Stauffer, Frederic and Ragot, Christian and Caravatti, Giorgio and Scheufler, Clemens and Hommel, Ulrich and Tiedt, Ralph and Beyer, Kim and Chen, Chao and 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

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