State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
Eur J Med Chem. 2024 Nov 5;277:116721. doi: 10.1016/j.ejmech.2024.116721. Epub 2024 Jul 30.
Ferroptosis is a unique type of non-apoptotic form of cell death characterized by increased lipid hydroperoxide levels. It has relevance for a number of pathological conditions including multiple organ injuries and degenerative diseases. GPX4 plays an important role in ferroptosis by repairing lipid hydroperoxides. Based on the reported allosteric sites, we obtained the GPX4 allosteric activator hit compound A9 through virtual screening. A9 can bind to GPX4 and prevent RSL3-induced lipid peroxidation production in HT-1080 cells. In addition, A9 can specifically rescue erastin-induced cell death. Further chemical modification and structure-activity relationship studies afforded the optimized compound C3. C3 showed the activity of alleviating myocardial injury in the doxorubicin-induced myocardial injury mouse model. This study demonstrated that inhibiting ferroptosis by activating GPX4 is expected to be a potential solution to treat myocardial injury.
铁死亡是一种独特的非细胞凋亡形式的细胞死亡，其特征是脂质过氧化物水平增加。它与多种病理状况有关，包括多器官损伤和退行性疾病。GPX4 通过修复脂质过氧化物在铁死亡中发挥重要作用。基于报道的别构位点，我们通过虚拟筛选获得了 GPX4 的别构激活剂命中化合物 A9。A9 可以与 GPX4 结合，并防止 RSL3 在 HT-1080 细胞中诱导的脂质过氧化产物的产生。此外，A9 可以特异性地挽救 erastin 诱导的细胞死亡。进一步的化学修饰和构效关系研究得到了优化的化合物 C3。C3 显示了在阿霉素诱导的心肌损伤小鼠模型中减轻心肌损伤的活性。本研究表明，通过激活 GPX4 抑制铁死亡有望成为治疗心肌损伤的一种潜在方法。
