jm0c01116_si_002.pdf (3.6 MB)
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 contributionposted on 2020-09-18, 11:35 authored by Hai-Shan Zhou, Lv-Bin Hu, Han Zhang, Wen-Xin Shan, Yan Wang, Xue Li, Tian Liu, Jing Zhao, Qi-Dong You, Zheng-Yu Jiang
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.
Compound 19novel indoline-based Keap 1-Nrf PPI...Comprehensive SAR analysiscardioprotective agentfactor erythroid 2-22 nMProteinindoline-based compoundsfluorescence polarization assaymouse modelsprotein leveldose-dependently upregulated genesoxidative stressesH 9cdrug-like propertiesKeap 1antioxidant response elementKeap 1-Nrf PPI inhibitorslipopolysaccharide-induced injuryIC 50target oxidativeKelch-likethermodynamics-guided optimizationNrf 2