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

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.