Design and characterization of a heterobifunctional degrader of KEAP1
The Kelch-like ECH-associated protein 1 (KEAP1) - nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway senses reactive oxygen species and regulates cellular oxidative stress. Inhibiting KEAP1 to activate the NRF2 antioxidant response has been proposed as a promising strategy to treat...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-02-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221323172200324X |
| _version_ | 1828065344800948224 |
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| author | Hao Chen Nghi H. Nguyen Charlene M. Magtoto Simon A. Cobbold Grace M. Bidgood Lizeth G. Meza Guzman Lachlan W. Richardson Jason Corbin Amanda E. Au Bernhard C. Lechtenberg Rebecca Feltham Kate D. Sutherland Christoph Grohmann Sandra E. Nicholson Brad E. Sleebs |
| author_facet | Hao Chen Nghi H. Nguyen Charlene M. Magtoto Simon A. Cobbold Grace M. Bidgood Lizeth G. Meza Guzman Lachlan W. Richardson Jason Corbin Amanda E. Au Bernhard C. Lechtenberg Rebecca Feltham Kate D. Sutherland Christoph Grohmann Sandra E. Nicholson Brad E. Sleebs |
| author_sort | Hao Chen |
| collection | DOAJ |
| description | The Kelch-like ECH-associated protein 1 (KEAP1) - nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway senses reactive oxygen species and regulates cellular oxidative stress. Inhibiting KEAP1 to activate the NRF2 antioxidant response has been proposed as a promising strategy to treat chronic diseases caused by oxidative stress. Here, we developed a proteolysis targeting chimera (PROTAC) that depletes KEAP1 from cells through the ubiquitin-proteasome pathway. A previously developed KEAP1 inhibitor and thalidomide were incorporated in the heterobifunctional design of the PROTAC as ligands for KEAP1 and CRBN recruitment, respectively. Optimization of the chemical composition and linker length resulted in PROTAC 14 which exhibited potent KEAP1 degradation with low nanomolar DC50 in HEK293T (11 nM) and BEAS-2B (<1 nM) cell lines. Furthermore, PROTAC 14 increased the expression of NRF2 regulated antioxidant proteins and prevented cell death induced by reactive oxygen species. Together, these results established a blueprint for further development of KEAP1-targeted heterobifunctional degraders and will facilitate the study of the biological consequences of KEAP1 removal from cells. This approach represents an alternative therapeutic strategy to existing treatments for diseases caused by oxidative stress. |
| first_indexed | 2024-04-10T23:13:31Z |
| format | Article |
| id | doaj.art-8bf601d4ee3e4a67b3cbbfafd936ded8 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-10T23:13:31Z |
| publishDate | 2023-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-8bf601d4ee3e4a67b3cbbfafd936ded82023-01-13T04:16:12ZengElsevierRedox Biology2213-23172023-02-0159102552Design and characterization of a heterobifunctional degrader of KEAP1Hao Chen0Nghi H. Nguyen1Charlene M. Magtoto2Simon A. Cobbold3Grace M. Bidgood4Lizeth G. Meza Guzman5Lachlan W. Richardson6Jason Corbin7Amanda E. Au8Bernhard C. Lechtenberg9Rebecca Feltham10Kate D. Sutherland11Christoph Grohmann12Sandra E. Nicholson13Brad E. Sleebs14The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, AustraliaDepartment of Medical Biology, The University of Melbourne, Parkville, 3010, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, AustraliaThe Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia; Corresponding author. The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3052, Victoria, Australia.The Kelch-like ECH-associated protein 1 (KEAP1) - nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway senses reactive oxygen species and regulates cellular oxidative stress. Inhibiting KEAP1 to activate the NRF2 antioxidant response has been proposed as a promising strategy to treat chronic diseases caused by oxidative stress. Here, we developed a proteolysis targeting chimera (PROTAC) that depletes KEAP1 from cells through the ubiquitin-proteasome pathway. A previously developed KEAP1 inhibitor and thalidomide were incorporated in the heterobifunctional design of the PROTAC as ligands for KEAP1 and CRBN recruitment, respectively. Optimization of the chemical composition and linker length resulted in PROTAC 14 which exhibited potent KEAP1 degradation with low nanomolar DC50 in HEK293T (11 nM) and BEAS-2B (<1 nM) cell lines. Furthermore, PROTAC 14 increased the expression of NRF2 regulated antioxidant proteins and prevented cell death induced by reactive oxygen species. Together, these results established a blueprint for further development of KEAP1-targeted heterobifunctional degraders and will facilitate the study of the biological consequences of KEAP1 removal from cells. This approach represents an alternative therapeutic strategy to existing treatments for diseases caused by oxidative stress.http://www.sciencedirect.com/science/article/pii/S221323172200324XPROTACKEAP1-NRF2 pathwayAntioxidantROSOxidative stress |
| spellingShingle | Hao Chen Nghi H. Nguyen Charlene M. Magtoto Simon A. Cobbold Grace M. Bidgood Lizeth G. Meza Guzman Lachlan W. Richardson Jason Corbin Amanda E. Au Bernhard C. Lechtenberg Rebecca Feltham Kate D. Sutherland Christoph Grohmann Sandra E. Nicholson Brad E. Sleebs Design and characterization of a heterobifunctional degrader of KEAP1 Redox Biology PROTAC KEAP1-NRF2 pathway Antioxidant ROS Oxidative stress |
| title | Design and characterization of a heterobifunctional degrader of KEAP1 |
| title_full | Design and characterization of a heterobifunctional degrader of KEAP1 |
| title_fullStr | Design and characterization of a heterobifunctional degrader of KEAP1 |
| title_full_unstemmed | Design and characterization of a heterobifunctional degrader of KEAP1 |
| title_short | Design and characterization of a heterobifunctional degrader of KEAP1 |
| title_sort | design and characterization of a heterobifunctional degrader of keap1 |
| topic | PROTAC KEAP1-NRF2 pathway Antioxidant ROS Oxidative stress |
| url | http://www.sciencedirect.com/science/article/pii/S221323172200324X |
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