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Discovery of 4-hydroxyl pyrazole derivatives as potent ferroptosis inhibitors
Danzhi Ying1, Xin Shen2, Shuqi Wang1
1College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Abstract:
Ferroptosis, an iron-dependent form of regulated cell death, has been well recognized as a pathogenic mechanism in driving many diseases, such as neurodegenerative disorders, ischemia-reperfusion (I/R) injury. Blocking ferroptosis has been emerging as a feasible therapeutic strategy for the prevention and treatment of these diseases. However, novel potent ferroptosis inhibitors remain to be developed for further clinical applications. In this study, we screened our in-house compound libraries by phenotypic assays and identified a 4-hydroxyl pyrazole derivative HW-3 with good ferroptosis inhibitory activity (EC50 = 120.1 ± 3.5 nM). Based on the structure of HW-3, a series of 4-hydroxyl pyrazole derivatives were further designed and synthesized. Among these compounds, compound 25 could significantly inhibit RSL3-induced ferroptosis with an EC50 value of 8.6 ± 2.2 nM in HT-1080 cells, which was 3-fold more potent than the classical ferroptosis inhibitor ferrostatin-1 (Fer-1) (EC50 = 23.4 ± 1.3 nM). The potent ferroptosis inhibitory activity of compound 25 was further validated in multiple additional cell lines. Our mechanistic study revealed that compound 25 inhibited ferroptosis via intrinsic radical-trapping antioxidative capacity. Taken together, the findings of our study demonstrate 4-hydroxyl pyrazole derivative 25 is a potent ferroptosis inhibitor, which holds a great therapeutic potential for further development.
Insights
Researchers identified a novel compound, 4-hydroxyl pyrazole derivative 25, that potently inhibits ferroptosis, a cell death pathway implicated in diseases. This new inhibitor shows promise as a therapeutic agent for various conditions.
Area of Science:
- Biochemistry
- Pharmacology
- Cell Biology
Background:
- Ferroptosis, an iron-dependent cell death, contributes to diseases like neurodegeneration and ischemia-reperfusion injury.
- Inhibiting ferroptosis is a promising therapeutic strategy, but new, effective inhibitors are needed.
Purpose of the Study:
- To discover and develop novel, potent ferroptosis inhibitors.
- To evaluate the therapeutic potential of newly synthesized 4-hydroxyl pyrazole derivatives.
Main Methods:
- Screening of in-house compound libraries using phenotypic assays.
- Design and synthesis of 4-hydroxyl pyrazole derivatives based on an initial hit compound (HW-3).
- In vitro evaluation of ferroptosis inhibition using cell-based assays (e.g., RSL3-induced ferroptosis in HT-1080 cells) and comparison with ferrostatin-1.
Main Results:
- Identified HW-3, a 4-hydroxyl pyrazole derivative, with good ferroptosis inhibitory activity (EC50 = 120.1 ± 3.5 nM).
- Synthesized a series of derivatives, with compound 25 showing significantly higher potency (EC50 = 8.6 ± 2.2 nM) than ferrostatin-1 (EC50 = 23.4 ± 1.3 nM).
- Compound 25 demonstrated potent ferroptosis inhibition across multiple cell lines via intrinsic radical-trapping antioxidative capacity.
Conclusions:
- 4-hydroxyl pyrazole derivative 25 is a highly potent inhibitor of ferroptosis.
- Compound 25 exhibits significant therapeutic potential for diseases associated with ferroptosis.
- Further development of compound 25 is warranted for clinical applications.
