Tang Jiaqin, Tie Xin, Zhi Shumeng, Wang Zhizhong, Zhao Qipeng, Qu Zhuo, Lu Guangyuan, Li Qin, Wu Yanran, Shi Ying
Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area (Ningxia Medical University), Ministry of Education, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China.
Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area (Ningxia Medical University), Ministry of Education, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China.
Bioorg Chem. 2024 Dec;153:107741. doi: 10.1016/j.bioorg.2024.107741. Epub 2024 Aug 31.
Oxidative stress is intricately linked to acute lung injury (ALI) and cerebral ischemic/reperfusion (I/R) injury. The Keap1 (Kelch-like ECH-Associating protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2)-ARE (antioxidant response element) signaling pathway, recognized as a crucial regulatory mechanism in oxidative stress, holds immense potential for the treatment of both diseases. In our laboratory, we initially screened a compound library and identified compound 3, which exhibited a dissociation constant of 5090 nM for Keap1. To enhance its binding affinity, we developed a novel 5-phenyl-1H-pyrrole-2-carboxylic acid Keap1-Nrf2 inhibitor through scaffold hopping from compound 3. Structure-activity relationship studies identified compound 19 as the most potent, with a K of 42.2 nM against Keap1. Furthermore, compound 19 showed significant protection against LPS-induced injury in BEAS-2B cells and promoted Nrf2 nuclear translocation. Subsequently, we investigated its therapeutic effects in mouse models of ALI injury. Compound 19 effectively alleviated symptoms at doses of 15 mg/kg for ALI injury. Additionally, it facilitated Nrf2 translocation to the nucleus, increased Nrf2 levels, and upregulated the expression of HO-1 and NQO1 in affected tissues.
氧化应激与急性肺损伤（ALI）和脑缺血/再灌注（I/R）损伤密切相关。Keap1（类 Kelch 样 ECH 相关蛋白 1）-Nrf2（核因子红细胞 2 相关因子 2）-ARE（抗氧化反应元件）信号通路被认为是氧化应激中的关键调节机制，在这两种疾病的治疗中具有巨大潜力。在我们实验室，我们最初筛选了一个化合物库并鉴定出化合物 3，其对 Keap1 的解离常数为 5090 nM。为了增强其结合亲和力，我们通过从化合物 3 进行骨架跃迁开发了一种新型的 5-苯基-1H-吡咯-2-羧酸 Keap1-Nrf2 抑制剂。构效关系研究确定化合物 19 是最有效的，对 Keap1 的 K 值为 42.2 nM。此外，化合物 19 对 BEAS-2B 细胞中脂多糖诱导的损伤显示出显著的保护作用，并促进 Nrf2 核转位。随后，我们在 ALI 损伤的小鼠模型中研究了其治疗效果。化合物 19 在 15 mg/kg 的剂量下对 ALI 损伤有效缓解症状。此外，它促进 Nrf2 转位至细胞核，增加 Nrf2 水平，并上调受影响组织中 HO-1 和 NQO1 的表达。
