Soluble epoxide hydrolase-targeting PROTAC activates AMPK and inhibits endoplasmic reticulum stress
Soluble epoxide hydrolase (sEH) is a drug target with the potential for therapeutic utility in the areas of inflammation, neurodegenerative disease, chronic pain, and diabetes, among others. Proteolysis-targeting chimeras (PROTACs) molecules offer new opportunities for targeting sEH, due to its capa...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223014658 |
| _version_ | 1797630672911728640 |
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| author | Mona Peyman Emma Barroso Andreea L. Turcu Francesc Estrany, Jr. Dáire Smith Javier Jurado-Aguilar Patricia Rada Christophe Morisseau Bruce D. Hammock Ángela M. Valverde Xavier Palomer Carles Galdeano Santiago Vázquez Manuel Vázquez-Carrera |
| author_facet | Mona Peyman Emma Barroso Andreea L. Turcu Francesc Estrany, Jr. Dáire Smith Javier Jurado-Aguilar Patricia Rada Christophe Morisseau Bruce D. Hammock Ángela M. Valverde Xavier Palomer Carles Galdeano Santiago Vázquez Manuel Vázquez-Carrera |
| author_sort | Mona Peyman |
| collection | DOAJ |
| description | Soluble epoxide hydrolase (sEH) is a drug target with the potential for therapeutic utility in the areas of inflammation, neurodegenerative disease, chronic pain, and diabetes, among others. Proteolysis-targeting chimeras (PROTACs) molecules offer new opportunities for targeting sEH, due to its capacity to induce its degradation. Here, we describe that the new ALT-PG2, a PROTAC that degrades sEH protein in the human hepatic Huh-7 cell line, in isolated mouse primary hepatocytes, and in the liver of mice. Remarkably, sEH degradation caused by ALT-PG2 was accompanied by an increase in the phosphorylated levels of AMP-activated protein kinase (AMPK), while phosphorylated extracellular-signal-regulated kinase 1/2 (ERK1/2) was reduced. Consistent with the key role of these kinases on endoplasmic reticulum (ER) stress, ALT-PG2 attenuated the levels of ER stress and inflammatory markers. Overall, the findings of this study indicate that targeting sEH with degraders is a promising pharmacological strategy to promote AMPK activation and to reduce ER stress and inflammation. |
| first_indexed | 2024-03-11T11:10:30Z |
| format | Article |
| id | doaj.art-5a58d1a50ea04ea4b20efc84ec133208 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-11T11:10:30Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-5a58d1a50ea04ea4b20efc84ec1332082023-11-12T04:38:50ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-12-01168115667Soluble epoxide hydrolase-targeting PROTAC activates AMPK and inhibits endoplasmic reticulum stressMona Peyman0Emma Barroso1Andreea L. Turcu2Francesc Estrany, Jr.3Dáire Smith4Javier Jurado-Aguilar5Patricia Rada6Christophe Morisseau7Bruce D. Hammock8Ángela M. Valverde9Xavier Palomer10Carles Galdeano11Santiago Vázquez12Manuel Vázquez-Carrera13Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, SpainDepartment of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, SpainInstitute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l′Alimentació, Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, SpainDepartment of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, SpainDepartment of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, SpainDepartment of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, SpainSpanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), Madrid, SpainDepartment of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616, United StatesDepartment of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616, United StatesSpanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), Madrid, SpainDepartment of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, SpainInstitute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, SpainInstitute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l′Alimentació, Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, SpainDepartment of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain; Correspondence to: Unitat de Farmacologia, Facultat de Farmàcia i Ciències de l′Alimentació, Av. Joan XXIII 27–31, E-08028 Barcelona, Spain.Soluble epoxide hydrolase (sEH) is a drug target with the potential for therapeutic utility in the areas of inflammation, neurodegenerative disease, chronic pain, and diabetes, among others. Proteolysis-targeting chimeras (PROTACs) molecules offer new opportunities for targeting sEH, due to its capacity to induce its degradation. Here, we describe that the new ALT-PG2, a PROTAC that degrades sEH protein in the human hepatic Huh-7 cell line, in isolated mouse primary hepatocytes, and in the liver of mice. Remarkably, sEH degradation caused by ALT-PG2 was accompanied by an increase in the phosphorylated levels of AMP-activated protein kinase (AMPK), while phosphorylated extracellular-signal-regulated kinase 1/2 (ERK1/2) was reduced. Consistent with the key role of these kinases on endoplasmic reticulum (ER) stress, ALT-PG2 attenuated the levels of ER stress and inflammatory markers. Overall, the findings of this study indicate that targeting sEH with degraders is a promising pharmacological strategy to promote AMPK activation and to reduce ER stress and inflammation.http://www.sciencedirect.com/science/article/pii/S0753332223014658SEHPROTACAMPKER stressHepatocyte |
| spellingShingle | Mona Peyman Emma Barroso Andreea L. Turcu Francesc Estrany, Jr. Dáire Smith Javier Jurado-Aguilar Patricia Rada Christophe Morisseau Bruce D. Hammock Ángela M. Valverde Xavier Palomer Carles Galdeano Santiago Vázquez Manuel Vázquez-Carrera Soluble epoxide hydrolase-targeting PROTAC activates AMPK and inhibits endoplasmic reticulum stress Biomedicine & Pharmacotherapy SEH PROTAC AMPK ER stress Hepatocyte |
| title | Soluble epoxide hydrolase-targeting PROTAC activates AMPK and inhibits endoplasmic reticulum stress |
| title_full | Soluble epoxide hydrolase-targeting PROTAC activates AMPK and inhibits endoplasmic reticulum stress |
| title_fullStr | Soluble epoxide hydrolase-targeting PROTAC activates AMPK and inhibits endoplasmic reticulum stress |
| title_full_unstemmed | Soluble epoxide hydrolase-targeting PROTAC activates AMPK and inhibits endoplasmic reticulum stress |
| title_short | Soluble epoxide hydrolase-targeting PROTAC activates AMPK and inhibits endoplasmic reticulum stress |
| title_sort | soluble epoxide hydrolase targeting protac activates ampk and inhibits endoplasmic reticulum stress |
| topic | SEH PROTAC AMPK ER stress Hepatocyte |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223014658 |
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