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J Med Chem. 2016 Apr 28;59(8):3991-4006. doi: 10.1021/acs.jmedchem.6b00228. Epub 2016 Apr 12.

Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery.

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Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, U.K.
GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.


KEAP1 is the key regulator of the NRF2-mediated cytoprotective response, and increasingly recognized as a target for diseases involving oxidative stress. Pharmacological intervention has focused on molecules that decrease NRF2-ubiquitination through covalent modification of KEAP1 cysteine residues, but such electrophilic compounds lack selectivity and may be associated with off-target toxicity. We report here the first use of a fragment-based approach to directly target the KEAP1 Kelch-NRF2 interaction. X-ray crystallographic screening identified three distinct "hot-spots" for fragment binding within the NRF2 binding pocket of KEAP1, allowing progression of a weak fragment hit to molecules with nanomolar affinity for KEAP1 while maintaining drug-like properties. This work resulted in a promising lead compound which exhibits tight and selective binding to KEAP1, and activates the NRF2 antioxidant response in cellular and in vivo models, thereby providing a high quality chemical probe to explore the therapeutic potential of disrupting the KEAP1-NRF2 interaction.

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