Design, Synthesis, and Structure-Activity Relationships of Indoline-Based Kelch-like ECH-Associated Protein 1-Nuclear Factor (Erythroid-Derived 2)-Like 2 (Keap1-Nrf2) Protein-Protein Interaction Inhibitors
Design, Synthesis, and Structure-Activity Relationships of Indoline-Based Kelch-like ECH-Associated Protein 1-Nuclear Factor (Erythroid-Derived 2)-Like 2 (Keap1-Nrf2) Protein-Protein Interaction Inhibitors
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基于二氢吲哚的 Kelch 样 ECH 相关蛋白 1-核因子（红细胞衍生 2）-样 2 (Keap1-Nrf2) 蛋白-蛋白相互作用抑制剂的设计、合成和构效关系
DOI：
10.1021/acs.jmedchem.0c01116
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发表时间：
2020
影响因子：
7.3
通讯作者：
Jiang Zheng-Yu
中科院分区：
文献类型：
--
作者：
Zhou Hai-Shan;Hu Lv-Bin;Zhang Han;Shan Wen-Xin;Wang Yan;Li Xue;Liu Tian;Zhao Jing;You Qi-Dong;Jiang Zheng-Yu
Keap 1（Kelch-like ECH-associated protein 1）-Nrf 2（nuclear factor erythroid 2-related factor 2）-ARE（antioxidant response element）通路是机体抗氧化应激的主要防御机制，直接阻断Keap 1-Nrf 2蛋白-蛋白相互作用（PPI）已成为治疗氧化应激相关疾病（包括心血管疾病）的有效策略。在这里，我们描述的设计，合成和结构-活性关系（SAR）的吲哚为基础的化合物作为有效的Keap 1-Nrf 2 PPI抑制剂。综合的SAR分析和药物导向的优化确定19 a为该系列中最有效的抑制剂，在竞争性荧光偏振测定中的IC 50为22 nM。进一步的评价表明19 a具有适当的药物样性质。化合物19剂量依赖性地上调Nrf 2及其下游标志物的基因和蛋白水平，并在H9 c2心肌细胞和小鼠模型中显示出针对脂多糖诱导的损伤的保护作用。总的来说，我们在这里报道了一种新的基于吲哚啉的Keap 1-Nrf 2 PPI抑制剂作为一种潜在的心脏保护剂。
The Keap1 (Kelch-like ECH-associated protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2)-ARE (antioxidant response element) pathway is the major defending mechanism against oxidative stresses, and directly disrupting the Keap1-Nrf2 protein–protein interaction (PPI) has been an attractive strategy to target oxidative stress-related diseases, including cardiovascular diseases. Here, we describe the design, synthesis, and structure–activity relationships (SARs) of indoline-based compounds as potent Keap1-Nrf2 PPI inhibitors. Comprehensive SAR analysis and thermodynamics-guided optimization identified19aas the most potent inhibitor in this series, with an IC50of 22 nM in a competitive fluorescence polarization assay. Further evaluation indicated the proper drug-like properties of19a. Compound19adose-dependently upregulated genes and protein level of Nrf2 as well as its downstream markers and showed protective effects against lipopolysaccharide-induced injury in both H9c2 cardiac cells and mouse models. Collectively, we reported here a novel indoline-based Keap1-Nrf2 PPI inhibitor as a potential cardioprotective agent.