Tetrazole-containing naphthalene bis-sulfonamide Keap1-Nrf2 interaction inhibitors with unexpected binding modes.

ABSTRACT: Naphthalene bis-sulfonamides are amongst the most studied inhibitors of the interaction between Kelch-like ECH-associated protein-1 (Keap1), a ubiquitination facilitator protein and the nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor associated with diverse cytoprotective responses. The compounds bind to the C-terminal Kelch domain of Keap1 and occupy the Nrf2 binding pocket, causing Nrf2 to accumulate and increase the expression of a battery of antioxidant response element genes. The binding modes of the compounds have been characterised through a series of X-ray crystallography and binding assay studies. In this work we have evaluated a series of symmetric and asymmetric naphthalene bis-sulfonamides and identified a tight binding acid/tetrazole derivative 25. W

SUBMITTER: Georgakopoulos ND 

PROVIDER: S-EPMC12664080 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature