2. Academic Validation
  3. Design, synthesis, and biological evaluation of quinolinyl-ureido-phenyl-hydrazide derivatives and quinolinyl-hydrazide derivatives as anticancer agents targeting Nur77-mediated ferroptosis

Design, synthesis, and biological evaluation of quinolinyl-ureido-phenyl-hydrazide derivatives and quinolinyl-hydrazide derivatives as anticancer agents targeting Nur77-mediated ferroptosis

  • Eur J Med Chem. 2025 Jul 5:291:117559. doi: 10.1016/j.ejmech.2025.117559.
Yan-Fang Gao 1,  Yi-Jing Yang 1,  Jing-Bo Qin 2,  Ming-Yue Yu 3,  Sheng-Wei Hu 1,  Hao-Fan Zhang 1,  Fan-Hong Lin 1,  Hong-Yu Hu 4,  Mei-Juan Fang 5,  Jin-Zhang Zeng 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China.
  • 2 State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong-Hong Kong-Macao University Joint Laboratory of the Interventional Medicine Foundation of Guangdong Province, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, China.
  • 3 Xingzhi College, Zhejiang Normal University, Lanxi, 321004, China; College of Chemistry and Bioengineering, Yichun, 336000, China.
  • 4 Xingzhi College, Zhejiang Normal University, Lanxi, 321004, China. Electronic address: huhongyu22@126.com.
  • 5 State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China. Electronic address: fangmj@xmu.edu.cn.
  • 6 State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China. Electronic address: jzzeng@xmu.edu.cn.
PMID: 40215561 DOI: 10.1016/j.ejmech.2025.117559
Abstract

In the recent decade, targeting Ferroptosis for Cancer therapy has attracted remarkable attention. Interestingly, the transcriptional regulator Nur77, a promising therapeutic target in Cancer, has been recently identified as a crucial regulator of Ferroptosis. However, no Ferroptosis inducer targeting Nur77 has been reported currently. In this study, we built upon our prior research on Nur77 modulator 4-PQBH to design and synthesize four series of new compounds, with the objective of developing novel Nur77-mediated Ferroptosis inducers. Among them, compound 8f exhibited the most potency against the tested Cancer cell lines, including human estrogen positive breast Cancer and triple-negative breast Cancer cell lines, while displaying lower toxicity towards human normal cell lines HaCaT and MCF-10A (IC50> 50 μM). Furthermore, 8f demonstrated superior Nur77-binding activity in comparison to the reference compound Csn-B, and it has the capacity to activate the Nur77-driven luciferase activity and increase the protein level of Nur77. Remarkably, 8f induced an increase in the levels of Reactive Oxygen Species (ROS), malondialdehyde (MDA), and lipid peroxidation, concurrently with a reduction in the expression of GPX4 protein, culminating in the induction of Ferroptosis in a Nur77-dependent manner. In vivo, 8f treatment has been observed to significantly suppress MCF7 xenograft tumor growth. Consequently, a novel Ferroptosis inducer targeting Nur77 (8f) is first reported as a potent anti-EPBC agent, providing may serve as a promising lead for further drug development targeting Nur77-mediated Ferroptosis.

Keywords

Anticancer agent; Ferroptosis; Hydrazide; Nur77; Quinoline.

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