Structure–Activity and Structure–Property Relationship and Exploratory in Vivo Evaluation of the Nanomolar Keap1–Nrf2 Protein–Protein Interaction Inhibitor

• Published in: Journal of medicinal chemistry Vol. 58; no. 16; pp. 6410 - 6421
• Main Authors: Jiang, Zheng-Yu, Xu, Li−Li, Lu, Meng-Chen, Chen, Zhi-Yun, Yuan, Zhen-Wei, Xu, Xiao-Li, Guo, Xiao-Ke, Zhang, Xiao-Jin, Sun, Hao-Peng, You, Qi-Dong
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.08.2015; Amer Chemical Soc
• Subjects: Activation, Metabolic - drug effects; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Cell Line; Chemistry, Medicinal; Cytokines - biosynthesis; Female; Humans; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - genetics; Kelch-Like ECH-Associated Protein 1; Life Sciences & Biomedicine; Lipopolysaccharides - antagonists & inhibitors; Mice; Mice, Inbred C57BL; Models, Molecular; NF-E2-Related Factor 2 - antagonists & inhibitors; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Pharmacology & Pharmacy; Protein Binding; RNA, Small Interfering - genetics; Science & Technology; Structure-Activity Relationship; AGENTS; PATHWAY; DISCOVERY; MOLECULAR-MECHANISMS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b00185

Directly disrupting the Keap1–Nrf2 protein–protein interaction (PPI) is an effective way to activate Nrf2. Using the potent Keap1–Nrf2 PPI inhibitor that was reported by our group, we conducted a preliminary investigation of the structure–activity and structure–property relationships of the ring systems to improve the drug-like properties. Compound 18e, which bore p-acetamido substituents on the side chain phenyl rings, was the best choice for balancing PPI inhibition activity, physicochemical properties, and cellular Nrf2 activity. Cell-based experiments with 18e showed that the Keap1–Nrf2 PPI inhibitor can activate Nrf2 and induce the expression of Nrf2 downstream proteins in an Nrf2-dependent manner. An exploratory in vivo experiment was carried out to further evaluate the anti-inflammatory effects of 18e in a LPS-challenged mouse model. The primary results indicated that 18e could reduce the level of circulating pro-inflammatory cytokines induced by LPS and relieve the inflammatory response.