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
- 8 October 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (19), 11149-11168
- https://doi.org/10.1021/acs.jmedchem.0c01116
Abstract
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.Funding Information
- China Association for Science and Technology
- National Natural Science Foundation of China (81773581, 81773639, 81930100)
- Ministry of Science and Technology of the People's Republic of China (2017ZX09302003, 2018ZX09711002)
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- Double First Class Innovation Team of China Pharmaceutical University (CPU2018GY02)
- ???Qing Lan??? Project of Jiangsu Province
- Program for Outstanding Scientific and Technological Innovation Team of Jiangsu Higher Education
- Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (SKLNMZZ202003)
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