Fernandez-Gines R, Encinar JA, Hayes JD, Oliva B, Rodriguez-Franco MI, Rojo AI, Cuadrado A

It is widely accepted that activating the transcription factor NRF2 will blast the physiological anti-inflammatory mechanisms, which will help combat pathologic inflammation. Much effort is being put in inhibiting the main NRF2 repressor, KEAP1, with either electrophilic small molecules or disrupters of the KEAP1/NRF2 interaction. However, targeting ?-TrCP, the non-canonical ...

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repressor of NRF2, has not been considered yet. After in silico screening of ?1 million compounds, we now describe a novel small molecule, PHAR, that selectively inhibits the interaction between ?-TrCP and the phosphodegron in transcription factor NRF2. PHAR upregulates NRF2-target genes such as Hmox1, Nqo1, Gclc, Gclm and Aox1, in a KEAP1-independent, but ?-TrCP dependent manner, breaks the ?-TrCP/NRF2 interaction in the cell nucleus, and inhibits the ?-TrCP-mediated in vitro ubiquitination of NRF2. PHAR attenuates hydrogen peroxide induced oxidative stress and, in lipopolysaccharide-treated macrophages, it downregulates the expression of inflammatory genes Il1b, Il6, Cox2, Nos2. In mice, PHAR selectively targets the liver and greatly attenuates LPS-induced liver inflammation as indicated by a reduction in the gene expression of the inflammatory cytokines Il1b, TNf, and Il6, and in F4/80-stained liver resident macrophages. Thus, PHAR offers a still unexplored alternative to current NRF2 activators by acting as a ?-TrCP/NRF2 interaction inhibitor that may have a therapeutic value against undesirable inflammation.

Date: Jul. 11, 2022

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