Discovery and optimization of 1,2,4-triazole derivatives as novel ferroptosis inhibitors
Jiawei Zhang1, Fang Lin1, Yijie Xiao1
1Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Department of Urology and Department of Cancer Center of the Second Affiliated Hospital, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China.
Abstract:
Ferroptosis is a novel form of regulated cell death characterized by iron-dependent lipid ROS accumulation, which is associated with various diseases, including acute organ injury, neurodegenerative disorders, and cancer. Pharmacological inhibition of ferroptosis has great potential for the treatment of these diseases. However, the clinical translation of many ferroptosis inhibitors is hindered by their inadequate activity or suboptimal pharmacokinetic profiles. In this study, several 1,2,4-triazole derivatives were identified as novel ferroptosis inhibitors through phenotypic screening of our in-house compound library. Among these compounds, NY-26 was found to significantly inhibit RSL3-induced ferroptosis in 786-O cells with nanomolar level (EC50 = 62 nM). The antiferroptotic activity of NY-26 was further validated across multiple cell lines. Mechanistic studies revealed that NY-26 inhibits ferroptosis through its intrinsic free radical-trapping antioxidant capacity. Additional results demonstrated that the triazole derivatives could effectively ameliorate ferroptosis-related pathological conditions in a mouse model of ConA-induced acute liver injury. Taken together, NY-26, tethering a novel 1,2,4-triazole scaffold, could be an effective ferroptosis inhibitor with great therapeutic potential for further investigation.
Insights
Researchers discovered novel 1,2,4-triazole derivatives that inhibit ferroptosis, a cell death pathway implicated in diseases like cancer and organ injury. The compound NY-26 shows significant potential as a therapeutic agent.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Ferroptosis is a regulated cell death mechanism driven by iron-dependent lipid reactive oxygen species (ROS) accumulation.
- This cell death pathway is implicated in various diseases, including acute organ injury, neurodegenerative disorders, and cancer.
- Current ferroptosis inhibitors face challenges in clinical translation due to insufficient efficacy or poor pharmacokinetic properties.
Purpose of the Study:
- To identify novel ferroptosis inhibitors from a compound library.
- To evaluate the therapeutic potential of newly discovered 1,2,4-triazole derivatives.
- To investigate the mechanism of action and efficacy of lead compounds in disease models.
Main Methods:
- Phenotypic screening of an in-house compound library to identify ferroptosis inhibitors.
- In vitro assessment of compound activity using RSL3-induced ferroptosis in 786-O cells.
- Validation of antiferroptotic activity across multiple cell lines.
- Mechanistic studies to elucidate the mode of action.
- In vivo evaluation in a ConA-induced acute liver injury mouse model.
Main Results:
- Several 1,2,4-triazole derivatives were identified as potent ferroptosis inhibitors.
- Compound NY-26 demonstrated significant inhibition of ferroptosis with nanomolar potency (EC50 = 62 nM).
- NY-26 functions by trapping free radicals, acting as an intrinsic antioxidant.
- The identified triazole derivatives ameliorated pathological conditions in a mouse model of acute liver injury.
Conclusions:
- NY-26, based on a novel 1,2,4-triazole scaffold, is a promising ferroptosis inhibitor.
- The compound exhibits potent antiferroptotic activity and a favorable mechanism of action.
- NY-26 holds significant therapeutic potential for treating ferroptosis-related diseases and warrants further investigation.
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