Design, Synthesis, and Evaluation of Triazole Derivatives That Induce Nrf2 Dependent Gene Products and Inhibit the Keap1–Nrf2 Protein–Protein Interaction

• Published in: Journal of medicinal chemistry Vol. 58; no. 18; pp. 7186 - 7194
• Main Authors: Bertrand, Hélène C, Schaap, Marjolein, Baird, Liam, Georgakopoulos, Nikolaos D, Fowkes, Adrian, Thiollier, Clarisse, Kachi, Hiroko, Dinkova-Kostova, Albena T, Wells, Geoff
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.09.2015; Amer Chemical Soc
• Subjects: Cell Line, Tumor; Chemical Sciences; Chemistry, Medicinal; Click Chemistry; Computer Simulation; Databases, Chemical; Dose-Response Relationship, Drug; Fluorescence Polarization; HEK293 Cells; Heme Oxygenase-1 - biosynthesis; Heme Oxygenase-1 - genetics; Humans; Intracellular Signaling Peptides and Proteins - chemistry; Intracellular Signaling Peptides and Proteins - metabolism; Isothiocyanates - chemistry; Isothiocyanates - pharmacology; Kelch-Like ECH-Associated Protein 1; Life Sciences; Life Sciences & Biomedicine; Molecular Docking Simulation; NAD(P)H Dehydrogenase (Quinone) - biosynthesis; NAD(P)H Dehydrogenase (Quinone) - genetics; NF-E2-Related Factor 2 - chemistry; NF-E2-Related Factor 2 - metabolism; Pharmacology & Pharmacy; Protein Binding; Science & Technology; Structure-Activity Relationship; Sulfoxides; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; UBIQUITINATION; OXIDATIVE STRESS; PEPTIDE INHIBITORS; KELCH DOMAIN; PATHWAY; DLG MOTIFS; RANDOMIZED CLINICAL-TRIAL; NRF2-KEAP1 COMPLEX; BINDING; DISCOVERY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b00602

The transcription factor Nrf2 regulates the expression of a large network of cytoprotective and metabolic enzymes and proteins. Compounds that directly and reversibly inhibit the interaction between Nrf2 and its main negative regulator Keap1 are potential pharmacological agents for a range of disease types including neurodegenerative conditions and cancer. We describe the development of a series of 1,4-diphenyl-1,2,3-triazole compounds that inhibit the Nrf2–Keap1 protein–protein interaction (PPI) in vitro and in live cells and up-regulate the expression of Nrf2-dependent gene products.