Structure-Activity Relationships and Molecular Docking Analysis of Mcl-1 Targeting Renieramycin T Analogues in Patient-derived Lung Cancer Cells
Structure-Activity Relationships and Molecular Docking Analysis of Mcl-1 Targeting Renieramycin T Analogues in Patient-derived Lung Cancer Cells
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DOI：
10.3390/cancers12040875
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发表时间：
2020-04-01
期刊：
影响因子：
5.2
通讯作者：
Chanvorachote, Pithi
中科院分区：
文献类型：
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作者：
Petsri, Korrakod;Yokoya, Masashi;Chanvorachote, Pithi
髓细胞白血病1 （Mcl-1）和b细胞淋巴瘤2 （Bcl-2）蛋白是癌症治疗的有希望的靶点。在此，我们研究了利尼霉素T （RT）及其类似物的构效关系（SARs），并进行了分子对接分析，确定了Mcl-1靶向的关键功能基团。RT对多种肺癌细胞和耐药原发癌细胞有较强的抗癌活性。RT通过抑制Mcl-1介导细胞凋亡，并降低原代细胞中Bcl-2的水平。在SAR研究中，我们合成了5种RT类似物，并测试了它们的抗癌和靶向Mcl-1和bcl -2的作用。其中只有两种(TM-（-)-18和TM-(-)-4a）具有Mcl-1缺失和部分降低Bcl-2的抗癌活性，而其他类似物则没有这种作用。RT结构的特定氰化物和苯环部分被确定为其mcl -1靶向活性的关键。计算分子对接表明，RT、TM-(-)-18和TM-(-)-4a与Mcl-1的结合亲和力较高，而TM-(-)-45与Mcl-1的结合亲和力最低，TM-(-)-45是一个有苯环但不含氰化物的化合物。由于Mcl-1有助于癌细胞逃避凋亡，这些数据鼓励进一步开发RT化合物以及设计用于治疗Mcl-1驱动的癌症的新药。
Myeloid cell leukemia 1 (Mcl-1) and B-cell lymphoma 2 (Bcl-2) proteins are promising targets for cancer therapy. Here, we investigated the structure-activity relationships (SARs) and performed molecular docking analysis of renieramycin T (RT) and its analogues and identified the critical functional groups of Mcl-1 targeting. RT have a potent anti-cancer activity against several lung cancer cells and drug-resistant primary cancer cells. RT mediated apoptosis through Mcl-1 suppression and it also reduced the level of Bcl-2 in primary cells. For SAR study, five analogues of RT were synthesized and tested for their anti-cancer and Mcl-1- and Bcl-2-targeting effects. Only two of them (TM-(-)-18 and TM-(-)-4a) exerted anti-cancer activities with the loss of Mcl-1 and partly reduced Bcl-2, while the other analogues had no such effects. Specific cyanide and benzene ring parts of RT's structure were identified to be critical for its Mcl-1-targeting activity. Computational molecular docking indicated that RT, TM-(-)-18, and TM-(-)-4a bound to Mcl-1 with high affinity, whereas TM-(-)-45, a compound with a benzene ring but no cyanide for comparison, showed the lowest binding affinity. As Mcl-1 helps cancer cells evading apoptosis, these data encourage further development of RT compounds as well as the design of novel drugs for treating Mcl-1-driven cancers.