Open AccessNew Potent DOT1L Inhibitors for in Vivo Evaluation in Mouse
Author(s) -
Frédéric Stauffer,
Andreas Weiss,
Clemens Scheufler,
Henrik Möbitz,
Christian Ragot,
Kim S. Beyer,
Keith Calkins,
Daniel Guthy,
Michael Kiffe,
Bernard Van Eerdenbrugh,
Ralph Tiedt,
Christoph Gaul
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00452
Subject(s) - in vivo , gene silencing , cancer research , ectopic expression , potency , biology , cancer , gene , computational biology , in vitro , pharmacology , genetics
In MLL-rearranged cancer cells, disruptor of telomeric silencing 1-like protein (DOT1L) is aberrantly recruited to ectopic loci leading to local hypermethylation of H3K79 and consequently misexpression of leukemogenic genes. A structure-guided optimization of a HTS hit led to the discovery of DOT1L inhibitors with subnanomolar potency, allowing testing of the therapeutic principle of DOT1L inhibition in a preclinical mouse tumor xenograft model. Compounds displaying good exposure in mouse and nanomolar inhibition of target gene expression in cells were obtained and tested in vivo.