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Updated: Feb 6, 2026

2 in 1: One-step Affinity Purification for the Parallel Analysis of Protein-Protein and Protein-Metabolite Complexes
Published on: August 6, 2018
Replacement of a Naphthalene Scaffold in Kelch-like ECH-Associated Protein 1 (KEAP1)/Nuclear Factor
Benjamin G Richardson1, Atul D Jain1, Haranatha R Potteti
1Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy , ‡Department of Pediatrics, College of Medicine , §UICentre for Drug Discovery , ⊥Mass Spectrometry Core at Research Resources Center , #University of Illinois Cancer Center , University of Illinois at Chicago , 833 South Wood Street , Chicago , Illinois 60612 , United States.
Abstract:
Activators of nuclear factor-erythroid 2-related factor 2 (NRF2) could lead to promising therapeutics for prevention and treatment of oxidative stress and inflammatory disorders. Ubiquitination and subsequent degradation of the transcription factor NRF2 is mediated by Kelch-like ECH-associated protein-1 (KEAP1). Inhibition of the KEAP1/NRF2 interaction with small molecules leads to NRF2 activation. Previously, we and others described naphthalene-based NRF2 activators, but the 1,4-diaminonaphthalene scaffold may not represent a drug-like scaffold. Paying particular attention to aqueous solubility, metabolic stability, potency, and mutagenicity, we modified a previously known, naphthalene-based nonelectrophilic NRF2 activator to give a series of non-naphthalene and heterocyclic scaffolds. We found that, compared to previously reported naphthalene-based compounds, a 1,4-isoquinoline scaffold provides a better mutagenic profile without sacrificing potency, stability, or solubility.
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