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Publication Abstract from PubMed

The oxidative stress response, gated by the protein-protein interaction of KEAP1 and NRF2, has garnered significant interest in the past decade. Misregulation in this pathway has been implicated in disease states such as multiple sclerosis, rheumatoid arthritis, and diabetic chronic wounds. Many of the known activators of NRF2 are electrophilic in nature and may operate through several biological pathways rather than solely through the activation of the oxidative stress response. Recently, our lab has reported a nonelectrophilic, monoacidic, naphthalene-based NRF2 activator which exhibited good potency in vitro. Herein, we report a detailed structure-activity relationship of naphthalene-based NRF2 activators, an X-ray crystal structure of our monoacidic KEAP1 inhibitor, and identification of an underexplored area of the NRF2 binding pocket of KEAP1.

Synthesis and Evaluation of Noncovalent Naphthalene-Based KEAP1-NRF2 Inhibitors.,Lazzara PR, Jain AD, Maldonado AC, Richardson B, Skowron KJ, David BP, Siddiqui Z, Ratia KM, Moore TW ACS Med Chem Lett. 2020 Feb 19;11(4):521-527. doi:, 10.1021/acsmedchemlett.9b00631. eCollection 2020 Apr 9. PMID:32292559^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.