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.,Journal of Medicinal Chemistry

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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.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-09 , DOI: 10.1021/acs.jmedchem.0c01116
Hai-Shan Zhou _{1,

2} , Lv-Bin Hu _{1,

2} , Han Zhang _{1,

2} , Wen-Xin Shan _{1,

2} , Yan Wang _{1,

2} , Xue Li _{1,

2} , Tian Liu _{1,

2} , Jing Zhao _{1,

2} , Qi-Dong You _{1,

2} , Zheng-Yu Jiang _{1,

2}

Affiliation

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 identified 19a as the most potent inhibitor in this series, with an IC₅₀ of 22 nM in a competitive fluorescence polarization assay. Further evaluation indicated the proper drug-like properties of 19a. Compound 19a dose-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.

中文翻译：

设计，合成和基于吲哚啉的Kelch样ECH相关蛋白1-核因子（类胡萝卜素衍生2）样2（Keap1-Nrf2）蛋白-蛋白质相互作用抑制剂的结构活性关系。

Keap1（类似于Kech的ECH相关蛋白1）-Nrf2（核因子类胡萝卜素2相关因子2）-ARE（抗氧化反应元件）途径是抵抗氧化应激的主要防御机制，并直接破坏Keap1-Nrf2蛋白–蛋白相互作用（PPI）已成为针对氧化应激相关疾病（包括心血管疾病）的一种有吸引力的策略。在这里，我们描述了作为有效的Keap1-Nrf2 PPI抑制剂的基于吲哚啉的化合物的设计，合成和构效关系（SAR）。全面的SAR分析和热力学指导的优化方法确定19a是该系列中最有效的抑制剂，IC ₅₀在竞争性荧光偏振分析中获得22 nM的峰。进一步评估表明19a具有适当的类药物特性。化合物19a剂量依赖性上调Nrf2的基因和蛋白水平及其下游标记，并在H9c2心脏细胞和小鼠模型中显示出对脂多糖诱导的损伤的保护作用。总的来说，我们在这里报告了一种新型的基于吲哚啉的Keap1-Nrf2 PPI抑制剂作为潜在的心脏保护剂。

更新日期：2020-10-08

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