Identification of novel small-molecule inhibitors targeting menin-MLL interaction, repurposing the antidiarrheal loperamide.
Identification of novel small-molecule inhibitors targeting menin-MLL interaction, repurposing the antidiarrheal loperamide.
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DOI：
10.1039/c6ob01248e
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发表时间：
2016-09
影响因子：
3.2
通讯作者：
Liyan Yue;Juanjuan Du;F. Ye;Z. Chen;Lianchun Li;F. Lian;Bidong Zhang;Yuanyuan Zhang;Hualiang Jiang;Kaixian Chen;Yuanchao Li;Bing Zhou;Naixia Zhang;Ya-xi Yang;C. Luo
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文献类型：
--
作者：
Liyan Yue;Juanjuan Du;F. Ye;Z. Chen;Lianchun Li;F. Lian;Bidong Zhang;Yuanyuan Zhang;Hualiang Jiang;Kaixian Chen;Yuanchao Li;Bing Zhou;Naixia Zhang;Ya-xi Yang;C. Luo
混合谱系白血病（MLL）重排的白血病，其中含有多种MLL融合蛋白，尽管最新的治疗方案有所改善，但预后不良。已报道Menin是MLL融合蛋白的致白血病活性所需的辅因子。因此，破坏menin和MLL之间的蛋白质-蛋白质相互作用代表了治疗MLL白血病的非常有前途的策略。通过使用基于形状的支架跳跃方法的menin-MLL抑制剂，我们发现抗脑膜炎药洛哌丁胺对menin-MLL相互作用显示出先前未报告的轻度抑制作用（IC 50 = 69 ± 3 μM）。为了重新利用这种药物，进行了一系列化学修饰分析，三种基于洛哌丁胺的类似物DC_YM21、DC_YM25和DC_YM26显示出更好的活性，IC 50值分别为0.83 ± 0.13 μM、0.69 ± 0.07 μM和0.66 ± 0.05 μM。进一步用DC_YM21处理证明了对增殖的有效和选择性阻断以及对具有MLL易位的白血病细胞的细胞周期停滞和分化的诱导，这证实了特定的作用机制。总之，报道了一种靶向menin-MLL相互作用的新型支架分子，它们可能作为MLL白血病的新的潜在治疗剂。
Leukemia with a mixed lineage leukemia (MLL) rearrangement, which harbors a variety of MLL fusion proteins, has a poor prognosis despite the latest improved treatment options. Menin has been reported to be a required cofactor for the leukemogenic activity of MLL fusion proteins. Thus, the disruption of the protein-protein interactions between menin and MLL represents a very promising strategy for curing MLL leukemia. Making use of menin-MLL inhibitors with a shape-based scaffold hopping approach, we have discovered that the antidiarrheal loperamide displays previously unreported mild inhibition for the menin-MLL interaction (IC50 = 69 ± 3 μM). In an effort to repurpose this drug, a series of chemical modification analyses was performed, and three of the loperamide-based analogues, DC_YM21, DC_YM25 and DC_YM26 displayed better activities with IC50 values of 0.83 ± 0.13 μM, 0.69 ± 0.07 μM and 0.66 ± 0.05 μM, respectively. Further treatment with DC_YM21 demonstrated potent and selective blockage of proliferation and induction of both cell cycle arrest and differentiation of leukemia cells harboring MLL translocations, which confirmed the specific mechanism of action. In conclusion, molecules of a novel scaffold targeting menin-MLL interactions were reported and they may serve as new potential therapeutic agents for MLL leukemia.