:
Herein, the underlying role of disruptor of telomeric silencing 1-like (DOT1L) as a therapeutic target for mixed
lineage leukemia (MLL)-rearranged were comprehensively clarified. DOT1L can be aberrantly recruited by MLL fusion
partner, thereby occasion several leukemia relevant genes over-expression, and eventually lead to leukemia. As the unique
histone methyltransferase (HMT), DOT1L possessed the function to specifically methylate H3K79, which was identified as
hallmark of active transcription. Accordingly, blockading of DOT1L has been recognized as an effective approach for cancer
treatment. Currently, nucleoside DOT1L inhibitors have been developed successfully with the only EPZ5676 entering phase
Ⅰ clinical trial in 2013, which was validated as ‘orphan drug’ toward MLL-rearranged leukemia by FDA. In order to find
compounds with better pharmacokinetic properties as DOT1L inhibitors, other types of non-nucleoside skeletons have also
been reported successively.
