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

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.