Yu Gang, Yu Jia, Zhou Yunyun, Liu Kun, Peng Xiaolin, Xu Guangcan, Chen Chao, Meng Xueling, Zeng Xiaoping, Wu Hui, Zan Ningning, Luo Heng, Xu Bixue
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Medical University, Guiyang, 550014, China.
Natural Products Research Center of Guizhou Province, Guiyang, 550014, China.
Mol Divers. 2025 Mar 28. doi: 10.1007/s11030-025-11175-w.
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.
设计并合成了一系列新型2-三氟甲基-4-氨基喹唑啉衍生物，并对其抗肿瘤活性进行了评估。其中，几种目标化合物对K562和LNCaP表现出纳摩尔级的抑制活性。同时，体外和体内活性评估结果表明，化合物9具有显著的选择性抗癌活性且毒性较低。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作用机制可能是通过抑制沃纳解旋酶（WRN）活性并影响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，显著下调WRN的表达，抑制MDM2/p53通路，使受损DNA无法修复，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损伤修复途径的依赖WRN的抗癌药物提供了基础。
