Duan, Hongliang Lee, Jae Wook Moon, Sung Won Arora, Daleep Li, Yu Lim, Hui-Ying Wang, Weidong 2024-01-20T03:31:36Z 2024-01-20T03:31:36Z 2021-09-05 2016-09-08 0022-2623 https://pubs.kist.re.kr/handle/201004/123684 Pancreatic insulin-producing beta-cell dysfunction and death plays central roles in the onset and progression of both type 1 and type 2 diabetes. Current antidiabetic drugs cannot halt the ongoing progression of beta-cell dysfunction and death. In diabetes, a major cause for the decline in beta-cell function and survival is endoplasmic reticulum (ER) stress. Here, we identified quinazoline derivatives as a novel class of beta-cell protective agents against ER stress-induced dysfunction and death. A series of quinazoline derivatives were synthesized from dichloroquiazoline utilizing a sequence of nucleophilic reactions. Through SAR optimization, 2,4-diaminoquinazoline compound 9c markedly protects beta-cells against ER stress-induced dysfunction and death with 80% maximum rescue activity and an EC50 value of 0.56 mu M. Importantly, 9c restores the ER stress-impaired glucose-stimulated insulin secretion response and survival in primary human islet beta-cells. We showed that 9c protects beta-cells by alleviating ER stress through the suppression of the induction of key genes of the unfolded protein response and apoptosis. English AMER CHEMICAL SOC UNFOLDED-PROTEIN RESPONSE INSULIN GENE-TRANSCRIPTION SMALL-MOLECULE MESSENGER-RNA SELECTIVE-INHIBITION CHRONIC EXPOSURE KINASE IRE1-ALPHA ACTIVATION EXPRESSION Discovery, Synthesis, and Evaluation of 2,4-Diaminoquinazolines as a Novel Class of Pancreatic beta-Cell-Protective Agents against Endoplasmic Reticulum (ER) Stress Article 10.1021/acs.jmedchem.6b00041 1 JOURNAL OF MEDICINAL CHEMISTRY, v.59, no.17, pp.7783 - 7800 JOURNAL OF MEDICINAL CHEMISTRY 59 17 7783 7800 scie scopus 000383111300007 2-s2.0-84986323480 Chemistry, Medicinal Pharmacology & Pharmacy Article UNFOLDED-PROTEIN RESPONSE INSULIN GENE-TRANSCRIPTION SMALL-MOLECULE MESSENGER-RNA SELECTIVE-INHIBITION CHRONIC EXPOSURE KINASE IRE1-ALPHA ACTIVATION EXPRESSION