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New potent DOT1L inhibitors for in vivo evaluation in mouse

Stauffer, Frederic and Weiss, Andreas and Scheufler, Clemens and Moebitz, Henrik and Ragot, Christian and Beyer, Kim and Calkins, Keith and Guthy, Daniel Alexander and Kiffe, Michael and Van Eerdenbrugh, Bernard and Tiedt, Ralph and Gaul, Christoph (2019) New potent DOT1L inhibitors for in vivo evaluation in mouse. ACS medicinal chemistry letters.

Abstract

In MLL-rearranged cancer cells, disruptor of telomeric silencing 1-like protein (DOT1L) is aberrantly recruited to ectop-ic loci leading to local hypermethylation of H3K79 and consequently misexpression of leukemogenic genes. A struc-ture-guided optimization of a HTS hit led to the discovery of DOT1L inhibitors with subnanomolar potency, allowing to test the therapeutic principle of DOT1L inhibition in a preclinical mouse tumor xenograft model. Compounds dis-playing good exposure in mouse and nanomolar inhibition of target gene expression in cell were obtained and tested in vivo

Item Type: Article
Keywords: Dot1L, lysine histone methyltransferase, inhibitor, HTS hit, structure-based design
Date Deposited: 24 Dec 2019 00:45
Last Modified: 24 Dec 2019 00:45
URI: https://oak.novartis.com/id/eprint/39714

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