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Design, synthesis, and induction of tumor ferroptosis activity of a novel FSP1 protein degrading agent
Yanhong Huang1, Qiao Liu2, Jinzhuo Li1
1Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, Hainan, 570228, China.
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.
Insights
Researchers developed a novel compound, 2307, that effectively degrades Ferroptosis Suppressor Protein 1 (FSP1), a key target for modulating ferroptosis. This compound shows promise for understanding and treating diseases linked to ferroptosis.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Ferroptosis is implicated in various diseases and is a key area for therapeutic development.
- Ferroptosis Suppressor Protein 1 (FSP1) regulates lipid peroxidation and is a potential drug target.
- GPX4 is another critical regulator of ferroptosis, acting in parallel with FSP1.
Purpose of the Study:
- To design and synthesize novel PROTAC degraders targeting FSP1.
- To evaluate the efficacy of these compounds in degrading FSP1 and inducing ferroptosis.
- To explore the therapeutic potential of FSP1-targeting compounds in disease treatment.
Main Methods:
- Design and synthesis of two classes of PROTAC degraders based on the FSP1 inhibitor iFSP1.
- Activity screening to identify lead compounds with potent FSP1 degradation.
- Utilized flow cytometry and confocal microscopy to assess lipid peroxide accumulation.
- Performed cellular assays to evaluate antiproliferative effects and synergy with GPX4 inhibitors.
- Analyzed mRNA expression of ferroptosis-related proteins.
Main Results:
- The lead compound, 2307, demonstrated potent FSP1 degradation via the ubiquitin-proteasome system (DC50 = 263.7 nM).
- Compound 2307 effectively induced intracellular lipid peroxide accumulation.
- Exhibited moderate antiproliferative effects and synergistic ferroptosis induction with GPX4 inhibitors.
- Upregulated mRNA expression of ferroptosis-related proteins upon treatment.
Conclusions:
- Compound 2307 is a potent FSP1 degrader and a valuable tool for studying ferroptosis.
- This compound shows promise for advancing therapeutic strategies targeting ferroptosis in disease.
- Further investigation into FSP1 modulation could lead to new drug development avenues.
