Turcu AL

References (2)

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.
ESTHER : Peyman_2023_Biomed.Pharmacother_168_115667
PubMedSearch : Peyman_2023_Biomed.Pharmacother_168_115667
PubMedID: 37826940
Gene_locus related to this paper: human-EPHX2

Title : A novel class of multitarget anti-Alzheimer benzohomoadamantanechlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors - Perez-Areales_2019_Eur.J.Med.Chem_180_613
Author(s) : Perez-Areales FJ , Turcu AL , Barniol-Xicota M , Pont C , Pivetta D , Espargaro A , Bartolini M , De Simone A , Andrisano V , Perez B , Sabate R , Sureda FX , Vazquez S , Munoz-Torrero D
Ref : Eur Journal of Medicinal Chemistry , 180 :613 , 2019
Abstract : The development of multitarget compounds against multifactorial diseases, such as Alzheimer's disease, is an area of very intensive research, due to the expected superior therapeutic efficacy that should arise from the simultaneous modulation of several key targets of the complex pathological network. Here we describe the synthesis and multitarget biological profiling of a new class of compounds designed by molecular hybridization of an NMDA receptor antagonist fluorobenzohomoadamantanamine with the potent acetylcholinesterase (AChE) inhibitor 6-chlorotacrine, using two different linker lengths and linkage positions, to preserve or not the memantine-like polycyclic unsubstituted primary amine. The best hybrids exhibit greater potencies than parent compounds against AChE (IC50 0.33nM in the best case, 44-fold increased potency over 6-chlorotacrine), butyrylcholinesterase (IC50 21nM in the best case, 24-fold increased potency over 6-chlorotacrine), and NMDA receptors (IC50 0.89muM in the best case, 2-fold increased potency over the parent benzohomoadamantanamine and memantine), which suggests an additive effect of both pharmacophoric moieties in the interaction with the primary targets. Moreover, most of these compounds have been predicted to be brain permeable. This set of biological properties makes them promising leads for further anti-Alzheimer drug development.
ESTHER : Perez-Areales_2019_Eur.J.Med.Chem_180_613
PubMedSearch : Perez-Areales_2019_Eur.J.Med.Chem_180_613
PubMedID: 31351393