2. Academic Validation
  3. Design, synthesis, and induction of tumor ferroptosis activity of a novel FSP1 protein degrading agent

Design, synthesis, and induction of tumor ferroptosis activity of a novel FSP1 protein degrading agent

  • Eur J Med Chem. 2026 Jan 15;302(Pt 1):118270. doi: 10.1016/j.ejmech.2025.118270.
Yanhong Huang 1,  Qiao Liu 2,  Jinzhuo Li 1,  Mingyu Cheng 3,  Rui Su 1,  Ziyi Jiao 1,  Sunkai Gu 1,  Qin Wang 1,  Wei Wang 1,  Fan Yang 1,  Yong Rao 1,  Ling Huang 4,  Yuqi Gao 5,  Congjun Xu 6
Affiliations

Affiliations

  • 1 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, Hainan, 570228, China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong First Medical University, Jinan, Shandong, 250117, China.
  • 3 School of Radiology, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, 271016, China.
  • 4 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, Hainan, 570228, China. Electronic address: Linghuang@hainanu.edu.cn.
  • 5 School of Radiology, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong, 271016, China; Department of Medicinal Chemistry, School of Pharmacy, State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong First Medical University, Jinan, Shandong, 250117, China. Electronic address: gaoyuqi@sdfmu.edu.cn.
  • 6 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, Hainan, 570228, China. Electronic address: congjunxu@hainanu.edu.cn.
PMID: 41172647 DOI: 10.1016/j.ejmech.2025.118270
Abstract

Ferroptosis, closely linked to the pathogenesis and progression of numerous diseases, has emerged as a significant frontier in drug discovery. FSP1, a key regulator of lipid peroxidation acting in parallel with GPX4, represents a promising therapeutic target for Ferroptosis modulation. In this study, we designed and synthesized two distinct classes of PROTAC degraders based on the FSP1 inhibitor iFSP1. Through activity screening, the lead compound 2307 demonstrated potent FSP1 degradation activity via the ubiquitin-proteasome system, achieving a DC50 value of 263.7 nM without exhibiting a hook effect. Flow cytometry and confocal microscopy experiments confirmed that 2307 significantly induces the accumulation of intracellular lipid peroxides. Furthermore, 2307 exhibits moderate antiproliferative effects, and cellular assays established its synergistic induction of Ferroptosis with GPX4 inhibitors. Notably, treatment with 2307 upregulated the mRNA expression of ferroptosis-related proteins. Collectively, compound 2307 serves as a valuable tool compound for investigating Ferroptosis mechanisms and advancing its therapeutic applications in drug development.

Keywords

Degraders; FSP1; Ferroptosis; PROTAC; Structure design.

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