Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Mol Cell. 2014 Jan 23;53(2):247-61. doi: 10.1016/j.molcel.2013.12.001. Epub 2014 Jan 2.
Here we report a comprehensive characterization of our recently developed inhibitor MM-401 that targets the MLL1 H3K4 methyltransferase activity. MM-401 is able to specifically inhibit MLL1 activity by blocking MLL1-WDR5 interaction and thus the complex assembly. This targeting strategy does not affect other mixed-lineage leukemia (MLL) family histone methyltransferases (HMTs), revealing a unique regulatory feature for the MLL1 complex. Using MM-401 and its enantiomer control MM-NC-401, we show that inhibiting MLL1 methyltransferase activity specifically blocks proliferation of MLL cells by inducing cell-cycle arrest, apoptosis, and myeloid differentiation without general toxicity to normal bone marrow cells or non-MLL cells. More importantly, transcriptome analyses show that MM-401 induces changes in gene expression similar to those of MLL1 deletion, supporting a predominant role of MLL1 activity in regulating MLL1-dependent leukemia transcription program. We envision broad applications for MM-401 in basic and translational research.
在这里，我们报告了对我们最近开发的抑制剂 MM-401 的全面表征，该抑制剂针对的是 MLL1 H3K4 甲基转移酶活性。MM-401 通过阻断 MLL1-WDR5 相互作用和复合物组装，能够特异性抑制 MLL1 活性。这种靶向策略不会影响其他混合谱系白血病（MLL）家族组蛋白甲基转移酶（HMTs），为 MLL1 复合物揭示了独特的调控特征。使用 MM-401 和其对映体对照 MM-NC-401，我们表明，通过诱导细胞周期停滞、凋亡和髓样分化，特异性抑制 MLL1 甲基转移酶活性可阻止 MLL 细胞的增殖，而对正常骨髓细胞或非 MLL 细胞没有一般毒性。更重要的是，转录组分析表明，MM-401 诱导的基因表达变化与 MLL1 缺失相似，支持 MLL1 活性在调节 MLL1 依赖性白血病转录程序中的主要作用。我们设想 MM-401 在基础和转化研究中有广泛的应用。
