The Kelch-like ECH-Associated Protein 1 (KEAP1)-Nuclear factor erythroid-2-related factor 2 (Nrf2) pathway is the master regulator of oxidative stress. Nrf2 is a transcription factor responsible for the transcription of over 500 genes associated with antioxidant, anti-inflammatory, and other cytoprotective mechanisms<i>. </i>Recent years have seen keen interest in the therapeutic intervention of this pathway for a variety of diseases, including respiratory, cardiovascular, renal, and neurodegenerative conditions. To date, this intervention has largely been accomplished using electrophilic compounds that covalently modify reactive cysteine residues on KEAP1, which prevents Nrf2 degradation and therefore activates that downstream protective response. Seeking an alternative strategy that would eliminate the potential risks of developing electrophlic compounds, including but not limited to off-target toxicity, we chose to pursue a different mode of action: directly disrupting the binding of Nrf2 to Keap1 at its native binding site in the Kelch domain. Identification of a lead series to target this protein-protein interaction was accomplished using a fragment-based discovery approach. Through a collaboration between GlaxoSmithKline and Astex Pharmaceuticals, X-ray crystallographic screening was utilized to identify fragment binders in the Kelch domain. A series of weak fragments hits identified “hot spots” within the Nrf2 binding site. The progression of these weak fragment hits to highly potent carboxylic acid-derived inhibitors such as KI-696 will be described.

Targeting the Kelch domain of KEAP1: A fragment-based discovery approach to identifying small molecule activators of Nrf2

255th National Meeting (2018)

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