The NRF2/ARE signalling pathway is a key mediator in oxidative stress and therefore a potential target for neuroprotective agents. The publication describes the identification of nonacidic tetrahydroisoquinolines (THIQs) that inhibit the interaction between NRF2 and its main negative regulator KEAP1. The approach utilized structural information from peptide screening at the P2 pocket, noncovalent small-molecule inhibitors, and the outcome from an explorative SAR at position 5 of THIQs to identify a series of neutral THIQ analogs that bind to KEAP1 in the low micromolar range.  X-ray crystallography studies reveal the novel binding mode of these molecules to KEAP1.