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J Med Chem. 2019 Sep 12;62(17):8028-8052. doi: 10.1021/acs.jmedchem.9b00723. Epub 2019 Aug 27.

A Comparative Assessment Study of Known Small-Molecule Keap1-Nrf2 Protein-Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity.

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Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , Universitetsparken 2 , DK-2100 Copenhagen , Denmark.
École Nationale Supérieure de Chimie de Rennes , 11 Allée de Beaulieu , CS 50837, Rennes Cedex 7 35708 , France.


Inhibiting the protein-protein interaction (PPI) between the transcription factor Nrf2 and its repressor protein Keap1 has emerged as a promising strategy to target oxidative stress in diseases, including central nervous system (CNS) disorders. Numerous non-covalent small-molecule Keap1-Nrf2 PPI inhibitors have been reported to date, but many feature suboptimal physicochemical properties for permeating the blood-brain barrier, while others contain problematic structural moieties. Here, we present the first side-by-side assessment of all reported Keap1-Nrf2 PPI inhibitor classes using fluorescence polarization, thermal shift assay, and surface plasmon resonance-and further evaluate the compounds in an NQO1 induction cell assay and in counter tests for nonspecific activities. Surprisingly, half of the compounds were inactive or deviated substantially from reported activities, while we confirm the cross-assay activities for others. Through this study, we have identified the most promising Keap1-Nrf2 inhibitors that can serve as pharmacological probes or starting points for developing CNS-active Keap1 inhibitors.

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