A series of novel 2-trifluoromethyl-4-aminoquinazoline derivatives were designed and synthesized, and their antitumor activities were evaluated. Among them, several target compounds exhibited nanomolar inhibitory activities against K562 and LNCaP. Meanwhile, the results of in vitro and in vivo activity evaluation showed that compound 9 had the significant selective anticancer activity and the lower toxicity. The target prediction and pathway analysis showed that the mechanism of compound 9 on the proliferation inhibitory activity of K562 and PC3 cells may be via inhibiting werner helicase (WRN) activity and affecting DNA damage repair. As expected, biological evaluation showed that compound 9 bind to WRN, significantly downregulated the expression of WRN, inhibited the MDM2/p53 pathway, to render the damaged DNA unrepaired, eventually causing mitotic arrest and cell death. Our findings provide a foundation for further research of trifluoromethyl-quinazoline-4-amines as WRN-dependent anticancer agents that targeting DNA damage repair pathway.

Graphical abstract

中文翻译：

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通过靶向 Werner 解旋酶发现含有三氟甲基的新型喹唑啉衍生物对抗细胞增殖

设计合成了一系列新型 2-三氟甲基-4-氨基喹唑啉衍生物，评价了其抗肿瘤活性。其中，几种靶标化合物对 K562 和 LNCaP 表现出纳摩尔抑制活性。同时，体外和体内活性评价结果表明，化合物 9 具有显著的选择性抗癌活性和较低的毒性。靶点预测和通路分析表明，化合物 9 对 K562 和 PC3 细胞增殖抑制活性的机制可能是通过抑制 werner 解旋酶 （WRN） 活性和影响 DNA 损伤修复。正如预期的那样，生物学评估表明化合物 9 与 WRN 结合，显着下调 WRN 的表达，抑制 MDM2/p53 通路，使受损的 DNA 未修复，最终导致有丝分裂停滞和细胞死亡。我们的研究结果为进一步研究三氟甲基-喹唑啉-4-胺作为靶向 DNA 损伤修复途径的 WRN 依赖性抗癌剂提供了基础。

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