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  3. Discovery of novel thiazolylhydrazone derivatives as potent anti-cancer agents inducing ferroptosis via direct NRF2 inhibition

Discovery of novel thiazolylhydrazone derivatives as potent anti-cancer agents inducing ferroptosis via direct NRF2 inhibition

  • Eur J Med Chem. 2025 Jun 28:297:117912. doi: 10.1016/j.ejmech.2025.117912.
Xiaolu Meng 1,  Tianqi Xu 2,  Lunan Xu 3,  Yixiang Du 3,  Fan Huo 3,  Anchang Jin 3,  Yajin Li 3,  Chao Yan 4,  Yaliang Zhang 5,  Tengfei Huang 6
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210023, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China.
  • 2 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China; Institute of Artificial Intelligence Biomedicine, Nanjing University, Nanjing, 210023, China.
  • 3 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China.
  • 4 Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210023, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China; Institute of Artificial Intelligence Biomedicine, Nanjing University, Nanjing, 210023, China. Electronic address: yanchao@nju.edu.cn.
  • 5 Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210023, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China. Electronic address: zhangyaliang@nju.edu.cn.
  • 6 Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210023, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China. Electronic address: htengfei1@gmail.com.
PMID: 40602226 DOI: 10.1016/j.ejmech.2025.117912
Abstract

Nuclear factor erythroid 2-related factor 2 (NRF2/NFE2L2) is a key transcription factor regulating antioxidant defense and iron metabolism. Its activation confers Ferroptosis resistance to Cancer cells and promotes tumor progression. In this study, we designed and synthesized a novel series of thiazolylhydrazone derivatives (1a-1g, 2a-2e, and 3a-3i) as NRF2 inhibitors and evaluated their antiproliferative activities against a panel of Cancer cell lines. Among them, PhcY emerged as the most potent compound. Molecular docking studies demonstrated its strong binding affinity to the NRF2 active site, indicating direct inhibition. PhcY induced Ferroptosis in MCF-7 breast Cancer cells via NRF2 inhibition. Mechanistic investigations revealed that PhcY disrupted cellular iron homeostasis, facilitated ferritin degradation, and ultimately triggered Ferroptosis. In vivo, PhcY demonstrated significant antitumor efficacy in MCF-7 xenograft-bearing mice at a dose of 10 mg/kg. These findings highlight the potential of thiazolylhydrazone derivatives, particularly PhcY, as NRF2-targeted Ferroptosis inducers for Cancer therapy.

Keywords

Autophagy; Ferritin degradation; Ferroptosis; NRF2; Thiazolylhydrazone derivatives.

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