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

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 repression 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.

SUBMITTER: Chen C

PROVIDER: S-EPMC4983735 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Chen Chao C Zhu Hugh H Stauffer Frédéric F Caravatti Giorgio G Vollmer Susanne S Machauer Rainer R Holzer Philipp P Möbitz Henrik H Scheufler Clemens C Klumpp Martin M Tiedt Ralph R Beyer Kim S KS Calkins Keith K Guthy Daniel D Kiffe Michael M Zhang Jeff J Gaul Christoph C

ACS medicinal chemistry letters 20160601 8

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 repression of leukemogenic genes and tumor growth inhibition. In the context of our Dot1L drug discovery program, high-throughput screening led to the ident ...[more]

PMID: 27563395

Dataset Information

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

Publications

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

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