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Drug-like biimidazole derivatives dually target c-MYC/BCL-2 G-quadruplexes and inhibit acute myeloid leukemia.
Bioorganic Chemistry ( IF 5.1 ) Pub Date : 2020-09-03 , DOI: 10.1016/j.bioorg.2020.104264
Ming-Hao Hu 1 , Bing-Ying Yu 1 , Xiaodong Wang 1 , Guangyi Jin 1
Affiliation  

Chemotherapy is the main approach for treating acute myeloid leukemia (AML). However, this therapy can cause severe side effects as well as drug resistance, hence calling for new therapeutic strategies. As c-MYC and BCL-2 are often overexpressed in AML, and synergism between c-MYC and BCL-2 promotes tumorigenesis, therefore, dual targeting of c-MYC/BCL-2 promoter G-quadruplexes (G4s) and then inhibiting the targeted gene expression would be a potential strategy in ALM treatment. In this work, in the search of dual ligands, we performed a screening assay with an in-house, imidazole-based compound library. Consequently, two drug-like biimidazole derivatives were identified as selective c-MYC/BCL-2 G4 binders, of which, BIM-2 was selected as the candidate for inhibiting AML cell growth. Then, BIM-2 was demonstrated to downregulate both c-MYC and BCL-2 expression, and thereby cause cell cycle arrest at G0/G1 phase and apoptosis in AML cells. Furthermore, the possible end-stacking binding modes between BIM-2 and c-MYC/BCL-2 G4s were revealed by NMR and molecular docking studies. Accordingly, this study provides a new class of drug-like dual-selective c-MYC/BCL-2 G4 ligands for the potential treatment of AML.



中文翻译:

药物样的联咪唑衍生物双重靶向c-MYC / BCL-2 G四联体并抑制急性髓细胞性白血病。

化学疗法是治疗急性髓细胞性白血病(AML)的主要方法。然而,这种疗法可能引起严重的副作用以及耐药性,因此需要新的治疗策略。由于c-MYCBCL-2在AML中通常过表达,并且c-MYCBCL-2之间的协同作用促进肿瘤发生,因此,c-MYC / BCL-2的双重靶向启动子G-四链体(G4s),然后抑制目标基因表达,将是ALM治疗的潜在策略。在这项工作中,在寻找双重配体的过程中,我们使用了一个基于咪唑的化合物库进行了筛选试验。因此,鉴定了两种药物样的联咪唑衍生物作为选择性c-MYC / BCL-2 G4结合剂,其中BIM-2被选为抑制AML细胞生长的候选物。然后,证明BIM-2下调c-MYCBCL-2表达,从而引起细胞周期停滞在G0 / G1期和AML细胞凋亡。此外,BIM-2之间可能的末端堆叠结合模式C-MYC / BCL-2台G4通过NMR和分子对接研究揭示。因此,本研究为潜在的AML治疗提供了一类新型的药物样双重选择性c-MYC / BCL-2 G4配体。

更新日期:2020-09-10
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