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New Potent DOT1L Inhibitors for in Vivo Evaluation in Mouse.

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.

SUBMITTER: Stauffer F

PROVIDER: S-EPMC6912874 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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New Potent DOT1L Inhibitors for <i>in Vivo</i> Evaluation in Mouse.

Stauffer Frédéric F Weiss Andreas A Scheufler Clemens C Möbitz Henrik H Ragot Christian C Beyer Kim S KS Calkins Keith K Guthy Daniel D Kiffe Michael M Van Eerdenbrugh Bernard B Tiedt Ralph R Gaul Christoph C

ACS medicinal chemistry letters 20191204 12

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 na ...[more]

PMID: 31857842

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