Design and optimisation of meta-substituted bis(arylsulfonamido)benzene inhibitors through a molecular hybridisation strategy targeting the Keap1-Nrf2 protein-protein interaction

Nrf2 is recognised as an attractive therapeutic target for oxidative stress-related disorders through its regulation of antioxidant gene transcription. Direct inhibition of Keap1-Nrf2 protein-protein interaction represents a promising strategy to modulate Nrf2 activity. Herein, we report the discovery of meta-substituted bis(arylsulfonamido)benzene derivatives using a molecular hybridisation strategy based onpotent inhibitors 2a and 3a. Among the initial hybrids, 7a demonstrated good potency in the FP assay, making it a suitable lead for SAR optimisation. Our study found 13b was the most potent analog, showing IC₅₀ values of 183.4 nM in the FP assay and 107.5 nM in the TR-FRET assay. It also demonstrated excellent metabolic stability, with 93.9% remaining after a 30 minute-incubation in human liver microsomes. Collectively, these results highlight 13b as a non-covalent Keap1-Nrf2PPI inhibitor, with balanced potency and metabolic stability, supporting its potential as a tractable scaffold for further optimisation to modulate the Nrf2 pathway.