Chen, Chao, Zhu, Hugh, Stauffer, Frederic, Caravatti, Giorgio, Vollmer, Susanne, Machauer, Rainer, Holzer, Philipp, Moebitz, Henrik, Scheufler, Clemens, Klumpp, Martin, Tiedt, Ralph, Beyer, Kim, Calkins, Keith, Kiffe, Michael, Guthy, Daniel Alexander, Zhang, Jeff and Gaul, Christoph (2016) The Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach. ACS Medicinal Chemistry Letters. ISSN 1948-58751948-5875

Abstract

Oncogenic MLL fusion proteins aberrantly recruit Dot1L, a histone methyltransferase, to ectopic loci, leading to local hypermethylation of H3K79 and misexpression of HoxA genes driving MLL-rearranged leukemias. Inhibition of the methyltransferase activity of Dot1L in this setting is predicted to reverse aberrant H3K79 methylation, leading to re-pression of leukemogenic genes and tumor growth inhibition. In the context of our Dot1L drug discovery program, high-throughput screening led to the identification of 2, a weak Dot1L inhibitor with an unprecedented, induced pocket binding mode. A medicinal chemistry campaign, strongly guided by structure-based consideration and ligand-based morphing, enabled the discovery of 12 and 13, potent, selective, and structurally completely novel Dot1L inhibitors.

Item Type:	Article
Keywords:	Dot1L, protein lysine methyltransferase, inhibitor, mixed lineage leukemia, protein structure-based design
Date Deposited:	08 Jun 2016 23:45
Last Modified:	04 Jul 2016 23:45
URI:	https://oak.novartis.com/id/eprint/27073