2. Academic Validation
  3. A small molecule NRF2 activator BC-1901S ameliorates inflammation through DCAF1/NRF2 axis

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

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: Liuy13@upmc.edu.
  • 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: chenb@upmc.edu.
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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