2. Academic Validation
  3. New Potent DOT1L Inhibitors for in Vivo Evaluation in Mouse

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

Affiliation

  • 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.

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