Hydroxybenzamide derivatives protect pancreatic β cell by suppressing unfolded protein response activation.

Autor: Eeda V; Division of Endocrinology, Department of Medicine, Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA., Rawal KN; Division of Endocrinology, Department of Medicine, Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA., Matlock HG; Department of Physiology, Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA., Herlea-Pana O; Division of Endocrinology, Department of Medicine, Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA., Lim HY; Department of Physiology, Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA., Wang W; Division of Endocrinology, Department of Medicine, Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA.
Jazyk: angličtina
Zdroj: Chemical biology & drug design [Chem Biol Drug Des] 2022 Aug; Vol. 100 (2), pp. 155-168. Date of Electronic Publication: 2022 Jun 07.
DOI: 10.1111/cbdd.14093
Abstrakt: Endoplasmic reticulum (ER) stress-induced Pancreatic β-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 β 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 β-cell protective activity against ER stress at a 100% maximal activity with EC 50 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 β-cell-protective scaffold thus provides a new promising modality for the potential for drug development for the treatment of diabetes.
(© 2022 John Wiley & Sons Ltd.)
Databáze: MEDLINE
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