Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
Mini Rev Med Chem. 2021;21(11):1337-1350. doi: 10.2174/1389557521666210111144357.
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.
在此，全面阐明了端粒沉默 1 样蛋白（DOT1L）作为混合谱系白血病（MLL）重排的治疗靶点的潜在作用。DOT1L 可以被 MLL 融合伙伴异常募集，从而导致几个与白血病相关的基因过度表达，最终导致白血病。作为独特的组蛋白甲基转移酶（HMT），DOT1L 具有特异性甲基化 H3K79 的功能，这被确定为活跃转录的标志。因此，阻断 DOT1L 已被认为是一种有效的癌症治疗方法。目前，已成功开发出核苷 DOT1L 抑制剂，其中唯一的 EPZ5676 于 2013 年进入 I 期临床试验，被 FDA 确认为针对 MLL 重排白血病的“孤儿药”。为了寻找具有更好药代动力学性质的 DOT1L 抑制剂化合物，也陆续报道了其他类型的非核苷骨架。
