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The Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach

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


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


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