Georgakopoulos, Nikolaos;
Talapatra, Sandeep;
Dikovskaya, Dina;
Dayalan Naidu, Sharadha;
Higgins, Maureen;
Gatliff, Jemma;
Ayhan, Aysel;
... Wells, Geoffrey; + view all
(2022)
Phenyl Bis-Sulfonamide Keap1-Nrf2 Protein–Protein Interaction Inhibitors with an Alternative Binding Mode.
Journal of Medicinal Chemistry
10.1021/acs.jmedchem.2c00457.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Phenyl Bis-Sulfonamide Keap1-Nrf2 Protein–Protein Interaction Inhibitors with an Alternative Binding Mode |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1021/acs.jmedchem.2c00457 |
| Publisher version: | https://doi.org/10.1021/acs.jmedchem.2c00457 |
| Language: | English |
| Additional information: | This work is licensed under an Attribution 4.0 International (CC BY 4.0) |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10148491 |
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