Phenyl Bis-Sulfonamide Keap1-Nrf2 Protein-Protein Interaction Inhibitors with an Alternative Binding Mode

TY - JOUR

T1 - Phenyl Bis-Sulfonamide Keap1-Nrf2 Protein-Protein Interaction Inhibitors with an Alternative Binding Mode

AU - Georgakopoulos, Nikolaos

AU - Talapatra, Sandeep

AU - Dikovskaya, Dina

AU - Dayalan Naidu, Sharadha

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, Geoffrey

N1 - Funding Information: G.W. would like to acknowledge the financial support from Cancer Research UK (C9344/A10268) (G.W.), the BBSRC (BB/L01923X/1) (A.T.D.-K., G.W.), the Bloomsbury Consortium (N.G., G.W.), UCL Knowledge Exchange and Innovation Fund (N.G., G.W.), MRC Proximity to Discovery (S.T., J.G., F.K.), Maplethorpe Trust (N.G.), Royal Society of Chemistry EnterprisePlus (R.N., N.G.), and UCL School of Pharmacy (G.W., F.K.). HRMS was obtained from the EPSRC UK National Mass Spectrometry Facility (NMSF) at Swansea University. We would like to thank Maria Walton and Raúl Pacheco-Gómez, Malvern Instruments, UK for assistance with the ITC experiments. We thank Diamond Light Source for access to beamlines I03 (MX12305) that contributed to the results presented here.

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 - Assays

KW - High-performance liquid chromatography

KW - Inhibitors

KW - Screening assays

UR - https://www.scopus.com/pages/publications/85131035859

U2 - 10.1021/acs.jmedchem.2c00457

DO - 10.1021/acs.jmedchem.2c00457

M3 - Article

C2 - 35549469

SN - 0022-2623

VL - 65

SP - 7380

EP - 7398

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 10

ER -