2024年1月15日 · A review of recently reported Keap1 inhibitors and Keap1–Nrf2 PPI inhibitors, as well as their mechanisms of action and structure-activity relationships. Summarize the future directions and application prospects of small molecule inhibitors of Keap1–Nrf2 axis for neurodegenerative diseases.

2021年4月1日 · To validate the utility of a PPI library for practical screenings and the effectiveness of ligand-based predicting methods for a PPI library, we focused on Kelch-like ECH-associated protein 1...

2022年6月20日 · KEAP1 functions as (i) a substrate adaptor for a Cullin 3 (CUL3)-based E3 ubiquitin ligase that targets NRF2 for ubiquitination and proteasomal degradation, and (ii) a cysteine-based sensor for a myriad of physiological and pharmacological NRF2 activators.

2021年7月5日 · An ultra-large structure-based virtual screening has discovered iKeap1 as a direct Keap1 inhibitor that can efficiently activate Nrf2 signaling.

In this review, we summarize known KEAP1‐NRF2 PPI inhibitors to date and the bases of their design highlighting the most important features of their respective interactions. We also discuss the preclinical pharmacological properties described for the most promising compounds.

The discovery of non-reactive direct small molecule inhibitors of the Keap1–Nrf2 pathway appears to be the most promising strategy due to the diminished possibility of toxic effects, as compared with indirect inhibitors, and increased stability and bioavailability, as compared with peptide inhibitors102, 103.

Activation of Nrf2 by disruption of Keap1 can enhance the antibacterial defence by macrophages and protect against sepsis. Keap1–Nrf2 protein–protein interaction (PPI) inhibitors are safe and effective Nrf2 activators. However, the specific function of Keap1–Nrf2 PPI inhibitors in sepsis remains unknown.

2023年12月28日 · Herein, we report a unique bivalent KEAP1 inhibitor, biKEAP1 (3), that engages cellular KEAP1 dimer to directly release sequestered NRF2 protein, leading to an instant NRF2 activation. 3 promotes the nuclear translocation of NRF2, directly suppressing proinflammatory cytokine transcription.

2020年9月15日 · Enhancing Nrf2 activity via disrupting Keap1-Nrf2 interaction is a furnish way for drug development. Various potent Keap1-Nrf2 inhibitors have been reported and some molecules showed proper drug-like properties. Keap1-Nrf2 inhibitors have shown the expected efficacy in several in vivo models.

2015年7月1日 · These non-covalent direct inhibitors of Keap1–Nrf2 PPI could potentially be developed into effective therapeutic or preventive agents for a variety of diseases and conditions. The Keap1–Nrf2– ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress.