Design, synthesis and evaluation of novel small molecules acting as Keap1-Nrf2 protein-protein interaction inhibitors

Abstract

Direct interference with Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 protein-protein interaction (PPI) has recently been introduced as an attractive approach to control life-threatening diseases like myocarditis. The present study aimed to investigate the potential application in myocarditis of a series of novel non-naphthalene derivatives as potential Keap1-Nrf2 PPI inhibitors. Our results indicated that the optimal compound K22 displayed the highest metabolic stability and showed notable Keap1-Nrf2 PPI inhibitory activities in vitro . K22 effectively triggered Nrf2 activation and increased the protein and mRNA expression of Nrf2-regulated genes in H9c2 cells. Moreover, pre-treatment with K22 was shown to mitigate LPS-induced damage to H9c2 cells, causing a marked decrease in the levels of inflammatory factors as well as reactive oxygen species (ROS). Furthermore, K22 was also shown to be non-mutagenic in the Ames test. Overall, our findings suggest that K22 may be a promising drug lead as a Keap1-Nrf2 PPI inhibitor for myocarditis treatment.

Medicinal Chemistry Insights into the Development of Small-Molecule Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1–Nrf2) Protein–Protein Interaction Inhibitors

“…114 Recently, a variety of Keap1−Nrf2 inhibitors harboring the 1,4-diaminobenzene scaffold were created. 115 At the beginning of the study, the researchers replaced the naphthalene scaffold of 8 with a single phenyl ring and changed one of the pmethoxyphenyl functionalities to the pyridine functionality. This asymmetric non-naphthalene derivative 31 (Figure 4) exhibited weak inhibitory activity with an IC 50 value of 31.55 μM in the FP assay.…”

“…Furthermore, compound 33 displayed no mutagenic activity in the Mini-Ames test. 115 Pyrazino[2,3-b]quinoxaline Derivative. Compound iKeap1 (34, Figure 6A) with a pyrazino[2,3-b]quinoxaline core was identified as a highly effective Keap1 inhibitor through an ultralarge-scale structure-based virtual screening followed by experimental validation.…”

“…Recently, a variety of Keap1–Nrf2 inhibitors harboring the 1,4-diaminobenzene scaffold were created . At the beginning of the study, the researchers replaced the naphthalene scaffold of 8 with a single phenyl ring and changed one of the p -methoxyphenyl functionalities to the pyridine functionality.…”

Structural investigation of Keap1–Nrf2 protein–protein interaction (PPI) inhibitors for treating myocarditis through molecular simulations

“…Sun et al developed a series of non-naphthalene scaffold-based Keap1-Nrf2 PPI inhibitors by analyzing the crystal structure of ligand and Keap1 Kelch-DC. 21 Inspired by their work, we propose a more refined strategy integrating 3D-QSAR, molecular docking, molecular dynamics simulation and ADME/T property prediction to develop novel inhibitors. In particular, in modeling research, we simultaneously introduced comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods, which can effectively guide molecular optimization and double predict molecular biological activity.…”

“…Sun et al developed a series of non-naphthalene scaffold-based Keap1–Nrf2 PPI inhibitors by analyzing the crystal structure of ligand and Keap1 Kelch-DC. 21…”