Wu Yunjie, Yang Lu, You Jing, Tian Chenyu, Yang Shengyong, Li Linli
Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan, 610041, China.
Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
Eur J Med Chem. 2025 Jan 15;282:117042. doi: 10.1016/j.ejmech.2024.117042. Epub 2024 Nov 12.
Ferroptosis is an iron-dependent regulated cell death, which has been implicated in the onset and progression of numerous diseases. Ferroptosis inhibitors are thought as potential agents for treating these related diseases. However, the majority of currently available ferroptosis inhibitors are antioxidants or iron chelators (called classical ferroptosis inhibitors), which might have potential risks of side effects during clinical use. Herein, we report the discovery of phenazine derivatives as a new class of non-classical ferroptosis inhibitors. Structure-activity relationship of these series compounds led to the discovery of the most active compound 13l with an EC value of 0.0007 μM. Mechanistically, 13l could inhibit NCOA4-mediated ferritinophagy, hence protecting cells from ferroptosis. Notably, in the acetaminophen-induced acute liver injury model, 13l showed an excellent therapeutic effect. Overall, this compound reported here could be a promising lead compound for drug discovery targeting ferroptosis.
铁死亡是一种铁依赖性的程序性细胞死亡，与多种疾病的发生和发展有关。铁死亡抑制剂被认为是治疗这些相关疾病的潜在药物。然而，目前大多数可用的铁死亡抑制剂是抗氧化剂或铁螯合剂（称为经典铁死亡抑制剂），在临床使用中可能存在潜在的副作用风险。在此，我们报告了吩嗪衍生物作为一类新型非经典铁死亡抑制剂的发现。这些系列化合物的构效关系导致发现了活性最高的化合物13l，其EC值为0.0007 μM。从机制上讲，13l可以抑制NCOA4介导的铁自噬，从而保护细胞免受铁死亡。值得注意的是，在对乙酰氨基酚诱导的急性肝损伤模型中，13l显示出优异的治疗效果。总体而言，本文报道的这种化合物可能是用于靶向铁死亡药物研发的一种有前景的先导化合物。
