New Potent DOT1L Inhibitors for in Vivo Evaluation in Mouse

  • ACS Med Chem Lett. 2019 Dec 4;10(12):1655-1660. doi: 10.1021/acsmedchemlett.9b00452.
Frédéric Stauffer  1 ,  Andreas Weiss  1 ,  Clemens Scheufler  1 ,  Henrik Möbitz  1 ,  Christian Ragot  1 ,  Kim S Beyer  1 ,  Keith Calkins  1 ,  Daniel Guthy  1 ,  Michael Kiffe  1 ,  Bernard Van Eerdenbrugh  1 ,  Ralph Tiedt  1 ,  Christoph Gaul  1
Affiliations
  • 1. Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
PMID: 31857842 DOI: 10.1021/acsmedchemlett.9b00452
Abstract

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.