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New potent DOT1L inhibitors for in vivo evaluation in mouse

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


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