TY - JOUR
T1 - Phenyl bis-sulfonamide Keap1-Nrf2 protein-protein interaction inhibitors with an alternative binding mode
AU - Georgakopoulos, Nikolaos D.
AU - Talapatra, Sandeep K.
AU - Dikovskaya, Dina
AU - Naidu, Sharadha Dayalan
AU - Higgins, Maureen
AU - Gatliff, Jemma
AU - Ayhan, Aysel
AU - Nikoloudaki, Roxani
AU - Schaap, Marjolein
AU - Valko, Klara
AU - Javid, Farideh
AU - Dinkova-Kostova, Albena T.
AU - Kozielski, Frank
AU - Wells, Geoff
PY - 2022/5/26
Y1 - 2022/5/26
N2 - Inhibitors of Kelch-like ECH-associated protein 1 (Keap1) increase the activity of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) by stalling its ubiquitination and degradation. This enhances the expression of genes encoding proteins involved in drug detoxification, redox homeostasis, and mitochondrial function. Nrf2 activation offers a potential therapeutic approach for conditions including Alzheimer's and Parkinson's diseases, vascular inflammation, and chronic obstructive airway disease. Non-electrophilic Keap1-Nrf2 protein-protein interaction (PPI) inhibitors may have improved toxicity profiles and different pharmacological properties to cysteine-reactive electrophilic inhibitors. Here, we describe and characterize a series of phenyl bis-sulfonamide PPI inhibitors that bind to Keap1 at submicromolar concentrations. Structural studies reveal that the compounds bind to Keap1 in a distinct "peptidomimetic" conformation that resembles the Keap1-Nrf2 ETGE peptide complex. This is different to other small molecule Keap1-Nrf2 PPI inhibitors, including bicyclic aryl bis-sulfonamides, offering a starting point for new design approaches to Keap1 inhibitors.
AB - Inhibitors of Kelch-like ECH-associated protein 1 (Keap1) increase the activity of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) by stalling its ubiquitination and degradation. This enhances the expression of genes encoding proteins involved in drug detoxification, redox homeostasis, and mitochondrial function. Nrf2 activation offers a potential therapeutic approach for conditions including Alzheimer's and Parkinson's diseases, vascular inflammation, and chronic obstructive airway disease. Non-electrophilic Keap1-Nrf2 protein-protein interaction (PPI) inhibitors may have improved toxicity profiles and different pharmacological properties to cysteine-reactive electrophilic inhibitors. Here, we describe and characterize a series of phenyl bis-sulfonamide PPI inhibitors that bind to Keap1 at submicromolar concentrations. Structural studies reveal that the compounds bind to Keap1 in a distinct "peptidomimetic" conformation that resembles the Keap1-Nrf2 ETGE peptide complex. This is different to other small molecule Keap1-Nrf2 PPI inhibitors, including bicyclic aryl bis-sulfonamides, offering a starting point for new design approaches to Keap1 inhibitors.
KW - Kelch-like ECH-associated protein 1 (Keap1)
KW - antioxidant response element (ARE)
KW - bis-sulfonamide inhibitors
U2 - 10.1021/acs.jmedchem.2c00457
DO - 10.1021/acs.jmedchem.2c00457
M3 - Article
C2 - 35549469
VL - 65
SP - 7380
EP - 7398
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 10
ER -