强效小分子 DOT1L 抑制剂选择性杀伤混合谱系白血病细胞。
Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor.
机构信息
Epizyme, Inc., Cambridge, MA 02139, USA.
出版信息
Cancer Cell. 2011 Jul 12;20(1):53-65. doi: 10.1016/j.ccr.2011.06.009.
Abstract
Mislocated enzymatic activity of DOT1L has been proposed as a driver of leukemogenesis in mixed lineage leukemia (MLL). The characterization of EPZ004777, a potent, selective inhibitor of DOT1L is reported. Treatment of MLL cells with the compound selectively inhibits H3K79 methylation and blocks expression of leukemogenic genes. Exposure of leukemic cells to EPZ004777 results in selective killing of those cells bearing the MLL gene translocation, with little effect on non-MLL-translocated cells. Finally, in vivo administration of EPZ004777 leads to extension of survival in a mouse MLL xenograft model. These results provide compelling support for DOT1L inhibition as a basis for targeted therapeutics against MLL.
摘要
DOT1L 酶活性定位错误被认为是混合谱系白血病（MLL）发生白血病的驱动因素。本文报道了 DOT1L 的一种有效、选择性抑制剂 EPZ004777 的特征。该化合物处理 MLL 细胞可选择性抑制 H3K79 甲基化并阻断白血病基因的表达。白血病细胞暴露于 EPZ004777 可选择性杀死携带 MLL 基因易位的细胞，对非 MLL 易位的细胞影响很小。最后，体内给予 EPZ004777 可延长 MLL 异种移植小鼠模型的存活时间。这些结果为 DOT1L 抑制作为针对 MLL 的靶向治疗的基础提供了有力支持。
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