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  3. RS-1: A Novel Hydrophobic Tagging GPX4 Degrader Inducing Ferroptosis and Suppressing Tumor Growth

RS-1: A Novel Hydrophobic Tagging GPX4 Degrader Inducing Ferroptosis and Suppressing Tumor Growth

  • ACS Omega. 2026 Feb 2;11(6):9098-9106. doi: 10.1021/acsomega.5c07348.
Qiqi Feng 1,  Xiaoru Zhang 1,  Yinkai Liu 1,  Hongyi Li 1,  Ruoxuan Liu 1,  Yaonan Wang 1,  Shurui Zhao 1,  Xiaoyi Zhang 1,  Ming Zhao 1 2
Affiliations

Affiliations

  • 1 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China.
  • 2 Beijing Laboratory of Biomedical Materials and Key Laboratory of Biomedical Materials of Natural Macromolecules, Department of Biomaterials, College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing 100026, China.
PMID: 41726627 DOI: 10.1021/acsomega.5c07348
Abstract

Glutathione Peroxidase 4 (GPX4), a critical regulator of Ferroptosis, represents an attractive therapeutic target in oncology. Here, we report the design, synthesis, and biological evaluation of RS-1, a hydrophobic tagging (HyT)-mediated GPX4 degrader. RS-1 induced dose- and time-dependent GPX4 degradation in HT1080 fibrosarcoma cells (DC50 = 8.9 nM), mechanistically dependent on the ubiquitin-proteasome system, as confirmed by MG-132 cotreatment. Ferrostatin-1 (Fer-1) rescued RS-1-induced cell death, validating Ferroptosis as the primary mechanism. Consistent with GPX4 loss, RS-1 elevated lipid peroxidation markers (Reactive Oxygen Species (ROS) and malondialdehyde (MDA)) in HT1080 cells. In vivo, RS-1 demonstrated potent antitumor efficacy in a 4T1 murine mammary carcinoma model, achieving 80.5% tumor growth inhibition (TGI). These findings establish RS-1 as a novel GPX4-targeted degrader with translational potential, offering a promising strategy to exploit Ferroptosis in Cancer therapy.

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