A small molecule NRF2 activator BC-1901S ameliorates inflammation through DCAF1/NRF2 axis
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 ubiq...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-05-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231720302962 |
| _version_ | 1818203769686458368 |
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| author | Yanwen Chen John W. Evankovich Travis B. Lear Ferhan Tuncer Jason R. Kennerdell Daniel P. Camarco Morgan S. Shishido Yuan Liu Bill B. Chen |
| author_facet | Yanwen Chen John W. Evankovich Travis B. Lear Ferhan Tuncer Jason R. Kennerdell Daniel P. Camarco Morgan S. Shishido Yuan Liu Bill B. Chen |
| author_sort | Yanwen Chen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T03:30:37Z |
| format | Article |
| id | doaj.art-ef47379132804ee6bcd98013701659b9 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-12T03:30:37Z |
| publishDate | 2020-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-ef47379132804ee6bcd98013701659b92022-12-22T00:39:55ZengElsevierRedox Biology2213-23172020-05-0132A small molecule NRF2 activator BC-1901S ameliorates inflammation through DCAF1/NRF2 axisYanwen Chen0John W. Evankovich1Travis B. Lear2Ferhan Tuncer3Jason R. Kennerdell4Daniel P. Camarco5Morgan S. Shishido6Yuan Liu7Bill B. Chen8Aging Institute, University of Pittsburgh, Pittsburgh, PA, 15213, USA; Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, ChinaAging Institute, University of Pittsburgh, Pittsburgh, PA, 15213, USA; Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA, 15213, USAAging 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, USAAging Institute, University of Pittsburgh, Pittsburgh, PA, 15213, USAAging Institute, University of Pittsburgh, Pittsburgh, PA, 15213, USAAging Institute, University of Pittsburgh, Pittsburgh, PA, 15213, USAAging Institute, University of Pittsburgh, Pittsburgh, PA, 15213, USAAging 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; Corresponding author. University of Pittsburgh Aging Institute, Department of Medicine, 558 Bridgeside Point 1, 100 Technology Drive, Pittsburgh, 15219, PA, USA.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; Corresponding author. University of Pittsburgh Aging Institute, Department of Medicine, 558 Bridgeside Point 1, 100 Technology Drive, Pittsburgh, 15219, PA, USA.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.http://www.sciencedirect.com/science/article/pii/S2213231720302962NRF2DCAF1High throughput screeningDrug discoveryUbiquitinationE3 ligase |
| spellingShingle | Yanwen Chen John W. Evankovich Travis B. Lear Ferhan Tuncer Jason R. Kennerdell Daniel P. Camarco Morgan S. Shishido Yuan Liu Bill B. Chen A small molecule NRF2 activator BC-1901S ameliorates inflammation through DCAF1/NRF2 axis Redox Biology NRF2 DCAF1 High throughput screening Drug discovery Ubiquitination E3 ligase |
| title | A small molecule NRF2 activator BC-1901S ameliorates inflammation through DCAF1/NRF2 axis |
| title_full | A small molecule NRF2 activator BC-1901S ameliorates inflammation through DCAF1/NRF2 axis |
| title_fullStr | A small molecule NRF2 activator BC-1901S ameliorates inflammation through DCAF1/NRF2 axis |
| title_full_unstemmed | A small molecule NRF2 activator BC-1901S ameliorates inflammation through DCAF1/NRF2 axis |
| title_short | A small molecule NRF2 activator BC-1901S ameliorates inflammation through DCAF1/NRF2 axis |
| title_sort | small molecule nrf2 activator bc 1901s ameliorates inflammation through dcaf1 nrf2 axis |
| topic | NRF2 DCAF1 High throughput screening Drug discovery Ubiquitination E3 ligase |
| url | http://www.sciencedirect.com/science/article/pii/S2213231720302962 |
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