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