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<p>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 <b>9</b> had the significant selective anticancer activity and the lower toxicity. The target prediction and pathway analysis showed that the mechanism of compound <b>9</b> 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 <b>9</b> 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.</p> Graphical abstract <p></p>

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Discovery of novel quinazoline derivatives containing trifluoromethyl against cell proliferation by targeting werner helicase

  • 期刊论文

  • 发表日期：

    2025年3月28日

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  • Gang Yu,
  • Jia Yu,
  • Yunyun Zhou,
  • Kun Liu,
  • Xiaolin Peng,
  • Guangcan Xu,
  • Chao Chen,
  • Xueling Meng,
  • Xiaoping Zeng,
  • Hui Wu,
  • Ningning Zan,
  • Heng Luo,
  • Bixue Xu

摘要

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