A small molecule NRF2 activator BC-1901S ameliorates inflammation through DCAF1/NRF2 axis

• Main Authors: Yanwen Chen, John W. Evankovich, Travis B. Lear, Ferhan Tuncer, Jason R. Kennerdell, Daniel P. Camarco, Morgan S. Shishido, Yuan Liu, Bill B. Chen
• Format: Article
• Language: English
• Published: Elsevier 2020-05-01
• Series: Redox Biology
• Subjects: NRF2; DCAF1; High throughput screening; Drug discovery; Ubiquitination; E3 ligase
• Online Access: http://www.sciencedirect.com/science/article/pii/S2213231720302962

NRF2 is a master regulator of cellular anti-oxidant and anti-inflammatory responses, and strategies to augment NRF2-dependent responses may beneficial in many diseases. Basal NRF2 protein level is constrained by constitutive KEAP1-mediated degradation, but in the presence of electrophiles, NRF2 ubiquitination is inhibited. Impeded NRF2 degradation increases NRF2 protein, resulting in up-regulation of anti-oxidant gene transcription, and decreased inflammation. KEAP1-independent mechanisms regulating NRF2 stability have also been reported. Here we employed an HTS approach and identified a small molecule, BC-1901S, that stabilized NRF2 and increased its activity. BC-1901S activated NRF2 by inhibiting NRF2 ubiquitination in a KEAP1-independent manner. It further increased NRF2-dependent anti-oxidant gene transcription, and exhibited anti-inflammatory effects in vitro and in vivo. Further, we identified a new NRF2-interacting partner, DDB1 and CUL4 Associated Factor 1 (DCAF1), an E3 ligase that targeted NRF2 for proteasomal degradation. Mechanistically, BC-1901S directly bound to DCAF1 and disrupted NRF2/DCAF1 interaction, thus activating NRF2. These findings provide new insights in NRF2 biology and NRF2 based anti-inflammatory therapy.