| Autor: |
Nikolaos Georgakopoulos, Sandeep Talapatra, Dina Dikovskaya, Sharadha Dayalan Naidu, Maureen Higgins, Jemma Gatliff, Aysel Ayhan, Roxani Nikoloudaki, Marjolein Schaap, Klara Valko, Farideh Javid, Albena T. Dinkova-Kostova, Frank Kozielski, Geoffrey Wells |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Journal of medicinal chemistry. 65(10) |
| ISSN: |
1520-4804 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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