Stauffer, Frederic, Scheufler, Clemens, Moebitz, Henrik, Gaul, Christoph, Ragot, Christian, Be, Celine, Fernandez, Cesar, 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