Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
Molecules. 2020 Sep 21;25(18):4318. doi: 10.3390/molecules25184318.
Both HDACs and Mnks play important role in translating multiple oncogenic signaling pathways during oncogenesis. As HDAC and Mnk are highly expressed in a variety of tumors; thus simultaneous inhibit HDAC and Mnk can increase the inhibition of tumor cell proliferation and provide a new way of inhibiting tumor growth. Based on the previous work and the merge pharmacophore method; we designed and synthesized a series of 4,6-disubstituted pyrido[3,2-]pyrimidine derivatives as HDAC and Mnk dual inhibitors. Among them; compound displayed good HDAC and Mnk inhibitory activity. In vitro antiproliferative assay; compound exhibited the best antiproliferative activity against human prostate cancer PC-3 cells. Docking study revealed that the pyrido[3,2-]pyrimidine framework and hydroxamic acid motif of compound were essential for maintaining the activity of HDAC and Mnk. These result indicated that was a potent Mnk /HDAC inhibitor and will be further researched.
HDAC 和 Mnks 在肿瘤发生过程中都对翻译多种致癌信号通路起着重要作用。由于 HDAC 和 Mnk 在多种肿瘤中高度表达；因此同时抑制 HDAC 和 Mnk 可以增加对肿瘤细胞增殖的抑制作用，并提供抑制肿瘤生长的新方法。基于以前的工作和合并药效团方法；我们设计并合成了一系列 4,6-取代的吡啶并[3,2-]嘧啶衍生物作为 HDAC 和 Mnk 的双重抑制剂。其中；化合物 显示出良好的 HDAC 和 Mnk 抑制活性。体外增殖抑制试验；化合物 对人前列腺癌 PC-3 细胞表现出最好的增殖抑制活性。对接研究表明，化合物的吡啶并[3,2-]嘧啶骨架和羟肟酸基序对于维持 HDAC 和 Mnk 的活性是必不可少的。这些结果表明 是一种有效的 Mnk/HDAC 抑制剂，将进一步研究。
