2. Academic Validation
  3. Dual-Targeting TrxR-EGFR Alkynyl-Au(I) Gefitinib Complex Induces Ferroptosis in Gefitinib-Resistant Lung Cancer via Degradation of GPX4

Dual-Targeting TrxR-EGFR Alkynyl-Au(I) Gefitinib Complex Induces Ferroptosis in Gefitinib-Resistant Lung Cancer via Degradation of GPX4

  • J Med Chem. 2025 Feb 19. doi: 10.1021/acs.jmedchem.4c02252.
Lingling Wang 1,  Xiaoyan Ma 2,  Ling Zhou 1,  Miao Luo 1,  Yunlong Lu 2,  Yawen Wang 2,  Pengdou Zheng 1,  Huiguo Liu 1,  Xiansheng Liu 1 3,  Wukun Liu 2,  Shuang Wei 1 3 4
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, National Health Commission (NHC) Key Laboratory of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China.
  • 2 Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.
  • 3 Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, P.R. China.
  • 4 Hubei Branch of National Clinical Research Center for Infectious Diseases, Wuhan Pulmonary Hospital (Wuhan Tuberculosis Prevention and Control Institute), Wuhan 430030, P.R. China.
PMID: 39968846 DOI: 10.1021/acs.jmedchem.4c02252
Abstract

Gefitinib exhibits significant clinical efficacy in patients with non-small cell lung Cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) sensitive mutations. However, its efficacy is severely limited by acquired resistance. Herein, we designed and synthesized a series of dual-targeting thioredoxin reductase (TrxR)-EGFR gold complexes by attaching a gold ligand to the parent structure of gefitinib, 4-anilinoquinazoline. Among them, L1Au2 exhibited significant activity against both gefitinib-sensitive and resistant lung cancers, effectively inhibiting tumor proliferation and promoting Apoptosis. Mechanistically, L1Au2 effectively inhibits TrxR and EGFR both in vitro and in vivo. Additionally, L1Au2 promotes the degradation of GPX4 protein via autophagolysosomal and proteasomal pathways, leading to Ferroptosis. Notably, L1Au2 also induces endoplasmic reticulum stress (ERS) and triggers immunogenic cell death (ICD). In conclusion, this study provides an innovative strategy for overcoming gefitinib resistance in lung Cancer by utilizing dual-targeting TrxR-EGFR alkynyl-Au(I) gefitinib derivatives, thereby offering a new approach for treating gefitinib-resistant lung Cancer.

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