Discovery of 2,4-diphenyl-substituted thiazole derivatives as PRMT1 inhibitors and investigation of their anti-cervical cancer effects.
Discovery of 2,4-diphenyl-substituted thiazole derivatives as PRMT1 inhibitors and investigation of their anti-cervical cancer effects.
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DOI：
10.1016/j.bmc.2023.117436
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发表时间：
2023-07
影响因子：
3.5
通讯作者：
Ziqi Zhao;Jungan Zhang;Yixin Ren;Luyao Dong;Han Wu;Wei Hong;Huoqiang Huang;Xinyi Yang;Zongran Pang;Hao Wang
中科院分区：
文献类型：
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作者：
Ziqi Zhao;Jungan Zhang;Yixin Ren;Luyao Dong;Han Wu;Wei Hong;Huoqiang Huang;Xinyi Yang;Zongran Pang;Hao Wang
宫颈癌是影响中年女性的最常见的癌症之一，需要发现新的药物来帮助临床治疗。作为蛋白质精氨酸甲基转移酶(PRMTs)家族的重要成员，PRMT1催化蛋白质精氨酸的甲基化，可影响癌细胞的多种生物学过程，如激活上皮-间充质转化(EMT)和获得对凋亡的抵抗。因此，PRMT1可被认为是治疗宫颈癌的潜在药物靶点。在本研究中，通过分子模拟发现了一个新的亚结合口袋，并通过在噻唑基上引入第三个取代来占据这个口袋，设计并合成了一系列潜在的PRMT1抑制剂。其中，两个化合物(ZJG51和ZJG58)对PRMT1表现出显著的抑制活性，而对PRMT5的抑制作用不明显。ZJG51和ZJG58对4种肿瘤细胞株的增殖均有较强的抑制作用，ZJG51对宫颈癌细胞株HeLa具有相对选择性。进一步的研究表明，ZJG51抑制HeLa细胞的迁移并诱导其凋亡。从机制上讲，ZJG51对PRMT1相关蛋白有明显的调控作用，提示ZJG51诱导细胞凋亡和抑制细胞迁移可能分别与激活Caspase9和抑制EMT有关。分子动力学模拟和自由能计算表明，ZJG51能稳定地与PRMT1结合，并预测了结合模式。这些数据表明，在五元环上引入第三取代基可能是未来PRMT1抑制剂结构优化的一个方向，而ZJG51可能是一个重要的先导化合物，为设计更有效的抑制剂提供信息。
Cervical cancer is one of the most common cancers that affects middle-aged women and the discovery of new drugs to aid clinical management is needed. As an important member of the protein arginine methyltransferases (PRMTs) family, PRMT1 catalyzes the methylation of protein arginine, which can influence multiple biological processes of cancer cells, such as activating epithelial-mesenchymal transformation (EMT) and acquiring resistance to apoptosis. Therefore, PRMT1 can be considered as a potential drug target for cervical cancer. In the current study, a new sub-binding pocket was discovered by molecular modeling, and by introducing a third substitute on the thiazole group to occupy this pocket, a series of compounds were designed and synthesized as potential PRMT1 inhibitors. Of these, two compounds (ZJG51 and ZJG58) exhibited significant inhibitory activities against PRMT1 without significantly inhibiting PRMT5. Both ZJG51 and ZJG58 displayed potent inhibitory effects on the proliferation of four cancer-derived cell lines and ZJG51 exerted relative selectivity against the cervical cancer cell line, HeLa. Further studies showed that ZJG51 inhibited migration and induce the apoptosis of HeLa cells. Mechanistically, ZJG51 significantly regulated PRMT1 related proteins, and indicated that the induction of apoptosis and inhibition of migration by ZJG51 may involve the activation of Caspase 9 and the inhibition of EMT, respectively. Molecular dynamic simulation and free energy calculation showed that ZJG51 can bind to PRMT1 stably and the binding mode was predicted. These data indicated that introducing the third substitute on the five-membered ring could be a future direction for structure-based optimization of PRMT1 inhibitors, and ZJG51 could be an important lead compound to inform the design of more potent inhibitors.