Abstract:

DOT1L is an epigenetic enzyme that can catalyze methyltransfer activity at histone 3 lysine 79 (H3K79). It is also found to be the first lysine methyltransferase without a SET domain. Research results show that methylation level of H3K79 can influence the expression of some genes, closely related to the development of acute myelocytic leukemia (AML). This work establishes a molecular-based high-throughout screening model for discovering novel DOT1L inhibitors. EPZ-5676 was used as positive control to optimize activity assay and ensure appropriate concentration of enzyme and substrate, and reaction time, etc. The assay was optimized, and the $Z'$-factor was about 0.54, indicating that a molecular-based high-throughout screening model for DOT1L inhibitors was successfully established.

Key words: disruptor of telomeric silencing 1-like (DOT1L), histone lysine methyltransferase, small molecule inhibitor, high-throughout screening (HTS)