Title:Nucleoside and Non-Nucleoside DOT1L Inhibitors: Dawn of MLLrearranged Leukemia
Volume: 21
Issue: 11
Author(s): Meng Cao, Tong Li, Yuxiang Chen and Xin Zhai*
Affiliation:
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016,China
Keywords:
Epigenetics, post-translational modification of histone, DOT1L, MLL-rearranged leukemia, nucleoside inhibitors,
non-nucleoside inhibitors.
Abstract: Herein, the underlying role of disruptor of telomeric silencing 1-like (DOT1L) as a therapeutic
target for mixed-lineage leukemia (MLL)-rearranged is comprehensively clarified. DOT1L can
be aberrantly recruited by an MLL fusion partner, thereby causing the over-expression, of several leukemia
relevant genes and eventually leading to leukemia. As the unique histone methyltransferase
(HMT), DOT1L possesses the function to specifically methylate H3K79, which was identified as a
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.
