Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 10, Issue 12, Pages 1655-1660Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.9b00452
Keywords
Dot1L; lysine histone methyltransferase; inhibitor; HTS hit; structure-based design
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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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