2. Academic Validation
  3. A potent GPX4 degrader to induce ferroptosis in HT1080 cells

A potent GPX4 degrader to induce ferroptosis in HT1080 cells

  • Eur J Med Chem. 2024 Feb 5:265:116110. doi: 10.1016/j.ejmech.2023.116110.
Haoze Song 1,  Jing Liang 2,  Yuanyuan Guo 2,  Yang Liu 2,  Kuiru Sa 2,  Guohong Yan 3,  Wen Xu 4,  Wei Xu 5,  Lixia Chen 6,  Hua Li 7
Affiliations

Affiliations

  • 1 Institute of Structural Pharmacology & TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China; Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 2 Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 3 Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou 350004, China. Electronic address: yghfjtcm@163.com.
  • 4 Institute of Structural Pharmacology & TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China. Electronic address: 2012029@fjtcm.edu.cn.
  • 5 Institute of Structural Pharmacology & TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China. Electronic address: 2000017@fjtcm.edu.cn.
  • 6 Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: syzyclx@163.com.
  • 7 Institute of Structural Pharmacology & TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China; Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: 2022041@fjtcm.edu.cn.
PMID: 38194774 DOI: 10.1016/j.ejmech.2023.116110
Abstract

Glutathione Peroxidase 4 (GPX4) is the most promising target for inducing Ferroptosis. GPX4-targeting strategies primarily focus on inhibiting its activity or adjusting its cellular level. However, small inhibitors have limitations due to the covalent reactive alkyl chloride moiety, which could lead to poor selectivity and suboptimal pharmacokinetic properties. Herein, we designed and synthesized a series of proteolysis targeting chimeras (PROTACs) by connecting RSL3, a small molecule inhibitor of GPX4, with six different ubiquitin Ligase ligands. As a highly effective degrader, compound 18a is a potent degrader (DC50, 48h = 1.68 μM, Dmax, 48h = 85 %). It also showed an obvious anti-proliferative effect with the IC50 value of 2.37 ± 0.17 μM in HT1080. Mechanism research showed that compound 18a formed a ternary complex with GPX4 and cIAP and induced the degradation of GPX4 through the ubiquitin-proteasome system pathway. Furthermore, compound 18a also induced the accumulation of lipid peroxides and mitochondrial depolarization, subsequently triggering Ferroptosis. Our work demonstrated the practicality and efficiency of the PROTAC strategy and offered a promising avenue for designing degraders to induce Ferroptosis in Cancer cells.

Keywords

Ferroptosis; GPX4 degradation; PROTAC; RSL3.

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