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.

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