Petsri Korrakod, Yokoya Masashi, Tungsukruthai Sucharat, Rungrotmongkol Thanyada, Nutho Bodee, Vinayanuwattikun Chanida, Saito Naoki, Takehiro Matsubara, Sato Ryo, Chanvorachote Pithi
Cell-based Drug and Health Products Development Research Unit, Chulalongkorn University, Bangkok 10330, Thailand.
Doctor of Philosophy Program in Interdisciplinary Pharmacology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand.
Cancers (Basel). 2020 Apr 3;12(4):875. doi: 10.3390/cancers12040875.
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.
髓样细胞白血病1（Mcl-1）和B细胞淋巴瘤2（Bcl-2）蛋白是很有前景的癌症治疗靶点。在此，我们研究了雷尼霉素T（RT）及其类似物的构效关系（SARs）并进行了分子对接分析，确定了靶向Mcl-1的关键官能团。RT对多种肺癌细胞和耐药原发性癌细胞具有强大的抗癌活性。RT通过抑制Mcl-1介导细胞凋亡，还降低了原代细胞中Bcl-2的水平。为了进行SAR研究，合成了RT的五种类似物，并测试了它们的抗癌以及靶向Mcl-1和Bcl-2的效果。其中只有两种（TM-(-)-18和TM-(-)-4a）具有抗癌活性，同时使Mcl-1缺失并部分降低了Bcl-2，而其他类似物则没有这种效果。RT结构中的特定氰基和苯环部分被确定对其靶向Mcl-1的活性至关重要。计算分子对接表明，RT、TM-(-)-18和TM-(-)-4a与Mcl-1具有高亲和力结合，而作为对照的具有苯环但没有氰基的化合物TM-(-)-45显示出最低的结合亲和力。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由Mcl-1驱动的癌症的新型药物。
