Both PLK1 and EEF2K are serine⁄threonine kinases that play important roles in the proliferation and programmed cell death of various types of cancer. They are highly expressed in breast cancer tissues. Based on the multiple-complexes generated pharmacophore models of PLK1 and homology models of EEF2K, the integrated virtual screening is performed to discover novel PLK1/EEF2K dual inhibitors. The top ten hit compounds are selected and tested in vitro, and five of them display PLK1 and EEF2K inhibition in vitro. Based on the docking modes of the most potent hit compound, a series of derivatives are synthesized, characterized and biological assayed on the PLK1, EEF2K as well as breast cancer cell proliferation models. Compound 18i with satisfied inhibitory potency are shifted to molecular mechanism studies contained molecular dynamics simulations, cell cycles, apoptosis and autophagy assays. Our results suggested that these novel PLK1/EEF2K dual inhibitors can be used as lead compounds for further development breast cancer chemotherapy.

PLK1 和 EEF2K 都是丝氨酸/苏氨酸激酶，在各种癌症的增殖和程序性细胞死亡中发挥重要作用。它们在乳腺癌组织中高度表达。基于多重复合物生成的PLK1药效团模型和EEF2K同源模型，进行集成虚拟筛选以发现新型PLK1/EEF2K双重抑制剂。选择前十名热门化合物并进行体外测试，其中五个在体外表现出 PLK1 和 EEF2K 抑制作用。基于最有效的命中化合物的对接模式，合成了一系列衍生物，并在PLK1、EEF2K以及乳腺癌细胞增殖模型上进行了表征和生物测定。具有满意抑制效力的化合物18i转向包括分子动力学模拟、细胞周期、细胞凋亡和自噬测定在内的分子机制研究。我们的结果表明，这些新型 PLK1/EEF2K 双重抑制剂可用作进一步开发乳腺癌化疗的先导化合物。