Hydroxybenzamide derivatives protect pancreatic ß cell by suppressing unfolded protein response activation.
Chem Biol Drug Des
; 100(2): 155-168, 2022 08.
Article
em En
| MEDLINE
| ID: mdl-35615997
ABSTRACT
Endoplasmic reticulum (ER) stress-induced Pancreatic ß-cell dysfunction and death plays important roles in the development of diabetes. The 1,2,3-triazole derivative 1 is one of only a few structures that have thus far been identified that protect ß cells against ER stress, but it is limited for its narrow activity range. In this study, we designed and synthesized a series of hydroxybenzamide (HBA) derivatives in which the triazole pharmacophore was substituted with an amide linker. Structure-activity relationship studies identified WO3i (3-hydroxy-N-(4-[trifluoromethyl]benzyl)benzamide) that possesses ß-cell protective activity against ER stress at a 100% maximal activity with EC50 at 0.19 µM). We showed that WO3i suppresses the expression of CHOP, a key mediator of ER stress-induced apoptosis, and the activation of apoptotic genes. Mechanistically, we further showed that WO3i suppresses the ER stress-induced activation of all three pathways of unfolded protein response-ATF6, IRE1α, and PERK. Identification of this novel ß-cell-protective scaffold thus provides a new promising modality for the potential for drug development for the treatment of diabetes.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Diabetes Mellitus
/
Células Secretoras de Insulina
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article