The adaptive stress response is a physiological mechanism that protects the body against electrophilic or oxidative stress by producing antioxidant enzymes. This response is controlled by the protein-protein interaction between the transcription factor NRF2 and its negative regulator KEAP1. Normal interaction of KEAP1 with NRF2 promotes NRF2’s degradation. Some electrophiles can disrupt this interaction by binding KEAP1, thus freeing, or “activating,” NRF2 so that it can transcriptionally upregulate detoxifying enzymes like heme oxygenase 1 and glutathione S-transferases. Because chronic oxidative stress is implicated in many diseases, including multiple sclerosis and diabetic wound healing, NRF2 activation has become an attractive pharmacological strategy. Many drug candidates are electrophiles that exhibit off-target activity. In contrast, our lab develops non-electrophilic NRF2 activators. Our starting point has been a non-electrophilic 1,4-diaminonaphthalene scaffold known to bind competitively to KEAP1’s Kelch domain, a crucial site for normal KEAP1-NRF2 interaction. Suggestive co-crystal structures have led us to develop a structure-activity relationship focused on cyclization of this scaffold. We hypothesize that constraining these molecules into their Kelch-bound conformation will enhance their binding affinities and membrane permeabilities. Two types of cyclic molecules were synthesized using hydrocarbon linkers in one of two ring substitution patterns. The linkers are stabilized at their terminal ends by either 1) amide bonds, or 2.) ether bonds. Preliminary data from in vitro binding assays suggest that amide-based linkages in meta-substituted bis-anilines are tolerated, especially when carboxymethyls are incorporated into the structure. This work identifies cyclization as a potentially useful strategy for studying the pharmacology of diaminonaphthalenes and similar scaffolds.

Cyclization-centered structure-activity relationship of a noncovalent inhibitor of the KEAP1-NRF2 interaction

2019 Spring National Meeting

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