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

  • Redox Biol. 2020 May:32:101485. doi: 10.1016/j.redox.2020.101485.
Yanwen Chen  1 ,  John W Evankovich  2 ,  Travis B Lear  3 ,  Ferhan Tuncer  4 ,  Jason R Kennerdell  4 ,  Daniel P Camarco  4 ,  Morgan S Shishido  4 ,  Yuan Liu  5 ,  Bill B Chen  6
Affiliations
  • 1. Aging Institute, University of Pittsburgh, Pittsburgh, PA, 15213, USA; Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
  • 2. Aging Institute, University of Pittsburgh, Pittsburgh, PA, 15213, USA; Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
  • 3. Aging Institute, University of Pittsburgh, Pittsburgh, PA, 15213, USA; Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA, 15213, USA; Department of Environmental and Occupational Health, School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
  • 4. Aging Institute, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
  • 5. Aging Institute, University of Pittsburgh, Pittsburgh, PA, 15213, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, 15213, USA. Electronic address: [email protected].
  • 6. Aging Institute, University of Pittsburgh, Pittsburgh, PA, 15213, USA; Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA, 15213, USA; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, 15213, USA. Electronic address: [email protected].
PMID: 32171724 DOI: 10.1016/j.redox.2020.101485
Abstract

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.

Keywords
DCAF1; Drug discovery; E3 ligase; High throughput screening; NRF2; Ubiquitination.
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