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Optimization of a fragment-based screening hit towards potent DOT1L inhibitors interacting in an induced binding pocket

Stauffer, Frederic and Scheufler, Clemens and Moebitz, Henrik and Gaul, Christoph and Ragot, Christian and Be, Celine and Fernandez, Cesar and Beyer, Kim and Tiedt, Ralph (2016) Optimization of a fragment-based screening hit towards potent DOT1L inhibitors interacting in an induced binding pocket. ACS Medicinal Chemistry Letters, 7 (8). pp. 730-734. ISSN DOI: 10.1021/acsmedchemlett.6b00168

Abstract

Mixed lineage leukemia (MLL) gene rearrangement induces leukemic transformation by ectopic recruitment of disruptor of telomeric silencing 1-like protein (DOT1L), a lysine histone methyltransferase, leading to local hypermeth-ylation of H3K79 and misexpression of genes (including HoxA) which drive the leukemic phenotype. A weak fragment-based screening hit identified by SPR was co-crystallized with DOT1L and optimized using structure-based ligand optimization to yield compound 8 (IC50 = 14 nM). This series of inhibitors is structurally not related to cofactor SAM and is not interacting with the SAM binding pocket but induces a pocket adjacent to the SAM binding site.

Item Type: Article
Keywords: Dot1L, lysine histone methyltransferase, inhibitor, fragment-based screen, structure-based design
Date Deposited: 07 Sep 2016 00:45
Last Modified: 07 Sep 2016 00:45
URI: https://oak.novartis.com/id/eprint/27139

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