Title : Soluble epoxide hydrolase-targeting PROTAC activates AMPK and inhibits endoplasmic reticulum stress - Peyman_2023_Biomed.Pharmacother_168_115667 |
Author(s) : Peyman M , Barroso E , Turcu AL , Estrany F, Jr. , Smith D , Jurado-Aguilar J , Rada P , Morisseau C , Hammock BD , Valverde A M , Palomer X , Galdeano C , Vazquez S , Vazquez-Carrera M |
Ref : Biomed Pharmacother , 168 :115667 , 2023 |
Abstract :
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. |
PubMedSearch : Peyman_2023_Biomed.Pharmacother_168_115667 |
PubMedID: 37826940 |
Gene_locus related to this paper: human-EPHX2 |
Inhibitor | ALT-PG2 |
Gene_locus | human-EPHX2 |
Peyman M, Barroso E, Turcu AL, Estrany F, Jr., Smith D, Jurado-Aguilar J, Rada P, Morisseau C, Hammock BD, Valverde A M, Palomer X, Galdeano C, Vazquez S, Vazquez-Carrera M (2023)
Soluble epoxide hydrolase-targeting PROTAC activates AMPK and inhibits endoplasmic reticulum stress
Biomed Pharmacother
168 :115667
Peyman M, Barroso E, Turcu AL, Estrany F, Jr., Smith D, Jurado-Aguilar J, Rada P, Morisseau C, Hammock BD, Valverde A M, Palomer X, Galdeano C, Vazquez S, Vazquez-Carrera M (2023)
Biomed Pharmacother
168 :115667