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Proton pump inhibitors selectively suppress MLL rearranged leukemia cells via disrupting MLL1-WDR5 protein-protein interaction.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2019-12-31 , DOI: 10.1016/j.ejmech.2019.112027 Wei-Lin Chen 1 , Dong-Dong Li 2 , Xin Chen 2 , Ying-Zhe Wang 2 , Jun-Jie Xu 2 , Zheng-Yu Jiang 3 , Qi-Dong You 3 , Xiao-Ke Guo 3
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2019-12-31 , DOI: 10.1016/j.ejmech.2019.112027 Wei-Lin Chen 1 , Dong-Dong Li 2 , Xin Chen 2 , Ying-Zhe Wang 2 , Jun-Jie Xu 2 , Zheng-Yu Jiang 3 , Qi-Dong You 3 , Xiao-Ke Guo 3
Affiliation
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Genetic rearrangements of the mixed lineage leukemia (MLL) leading to oncogenic MLL-fusion proteins (MLL-FPs). MLL-FPs occur in about 10% of acute leukemias and are associated with dismal prognosis and treatment outcomes which emphasized the need for new therapeutic strategies. In present study, by a cell-based screening in-house compound collection, we disclosed that Rabeprazole specially inhibited the proliferation of leukemia cells harboring MLL-FPs with little toxicity to non-MLL cells. Mechanism study showed Rabeprazole down-regulated the transcription of MLL-FPs related Hox and Meis1 genes and effectively inhibited MLL1 H3K4 methyltransferase (HMT) activity in MV4-11 cells bearing MLL-AF4 fusion protein. Displacement of MLL1 probe from WDR5 protein suggested that Rabeprazole may inhibit MLL1 HMT activity through disturbing MLL1-WDR5 protein-protein interaction. Moreover, other proton pump inhibitors (PPIs) also indicated the inhibition activity of MLL1-WDR5. Preliminary SARs showed the structural characteristics of PPIs were also essential for the activities of MLL1-WDR5 inhibition. Our results indicated the drug reposition of PPIs for MLL-rearranged leukemias and provided new insight for further optimization of targeting MLL1 methyltransferase activity, the MLL1-WDR5 interaction or WDR5.
中文翻译：
质子泵抑制剂通过破坏MLL1-WDR5蛋白质-蛋白质相互作用来选择性抑制MLL重排的白血病细胞。
混合谱系白血病（MLL）的遗传重排导致致癌性MLL融合蛋白（MLL-FPs）。MLL-FPs发生在约10％的急性白血病中，并且与不良的预后和治疗结果相关，这强调了对新治疗策略的需求。在目前的研究中，通过基于细胞的内部筛选化合物的收集，我们公开了雷贝拉唑特别抑制具有MLL-FP的白血病细胞的增殖，对非MLL细胞的毒性很小。机制研究表明，雷贝拉唑下调了MLL-FPs相关Hox和Meis1基因的转录，并有效抑制了带有MLL-AF4融合蛋白的MV4-11细胞中MLL1 H3K4甲基转移酶（HMT）的活性。从WDR5蛋白上取代MLL1探针表明，雷贝拉唑可能通过干扰MLL1-WDR5蛋白质-蛋白质相互作用来抑制MLL1 HMT活性。此外，其他质子泵抑制剂（PPI）也表明了MLL1-WDR5的抑制活性。初步的SAR显示，PPI的结构特征对于抑制MLL1-WDR5的活性也必不可少。我们的结果表明，针对MLL重排的白血病，PPI的药物重新定位为进一步优化靶向MLL1甲基转移酶活性，MLL1-WDR5相互作用或WDR5提供了新的见识。
更新日期：2020-01-01
中文翻译：
质子泵抑制剂通过破坏MLL1-WDR5蛋白质-蛋白质相互作用来选择性抑制MLL重排的白血病细胞。
混合谱系白血病（MLL）的遗传重排导致致癌性MLL融合蛋白（MLL-FPs）。MLL-FPs发生在约10％的急性白血病中，并且与不良的预后和治疗结果相关，这强调了对新治疗策略的需求。在目前的研究中，通过基于细胞的内部筛选化合物的收集，我们公开了雷贝拉唑特别抑制具有MLL-FP的白血病细胞的增殖，对非MLL细胞的毒性很小。机制研究表明，雷贝拉唑下调了MLL-FPs相关Hox和Meis1基因的转录，并有效抑制了带有MLL-AF4融合蛋白的MV4-11细胞中MLL1 H3K4甲基转移酶（HMT）的活性。从WDR5蛋白上取代MLL1探针表明，雷贝拉唑可能通过干扰MLL1-WDR5蛋白质-蛋白质相互作用来抑制MLL1 HMT活性。此外，其他质子泵抑制剂（PPI）也表明了MLL1-WDR5的抑制活性。初步的SAR显示，PPI的结构特征对于抑制MLL1-WDR5的活性也必不可少。我们的结果表明，针对MLL重排的白血病，PPI的药物重新定位为进一步优化靶向MLL1甲基转移酶活性，MLL1-WDR5相互作用或WDR5提供了新的见识。
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