The Discovery of GSK3227634: A Potent Inhaled Inhibitor of the KEAP1/NRF2 Protein–Protein Interaction for the Treatment of Chronic Obstructive Pulmonary Disease

Abstract KEAP1 is the key regulator of the NRF2-mediated cytoprotective response and a target for pathologies involving oxidative stress. Compounds that covalently modify KEAP1 to activate NRF2 are clinically validated; however, their chemical reactivity may drive increased off–target activity. A more selective approach involves inhibition of the KEAP1-NRF2 protein–protein interaction as exemplified by our previous bis-aryl lead KI-696 (4). We now describe the lead optimization of the bis-aryl series that focused on increasing the population of the bioactive conformation of the free ligand to drive potency while optimizing overall physicochemical properties. This resulted in the discovery of GSK3227634 (5), an ultrahigh-affinity noncovalent inhibitor of KEAP1-NRF2 (surface plasmon resonance pKd = 10.9) and the first NRF2 activator to demonstrate target engagement and efficacy in preclinical models of oxidative stress via direct delivery to the lung. Compound 5 therefore represents a novel potential agent to treat lung diseases involving oxidative stress, such as chronic obstructive pulmonary disease.