title: Identification of 1,2,3-triazole derivatives that protect pancreatic β cells against endoplasmic reticulum stress-mediated dysfunction and death through the inhibition of C/EBP-homologous protein expression.
abstract: The C/EBP-homologous protein (CHOP) acts as a mediator of endoplasmic reticulum (ER) stress-induced pancreatic insulin-producing β cell death, a key element in the pathogenesis of diabetes. Chemicals that inhibit the expression of CHOP might therefore protect β cells from ER stress-induced apoptosis and prevent or ameliorate diabetes. Here, we used high-throughput screening to identify a series of 1,2,3-triazole amide derivatives that inhibit ER stress-induced CHOP-luciferase reporter activity. Our SAR studies indicate that compounds with an N,1-diphenyl-5-methyl-1H-1,2,3-triazole-4-carboxamide backbone potently protect β cell against ER stress. Several representative compounds inhibit ER stress-induced up-regulation of CHOP mRNA and protein, without affecting the basal level of CHOP expression. We further show that a 1,2,3-triazole derivative 4e protects β cell function and survival against ER stress in a CHOP-dependent fashion, as it is inactive in CHOP-deficient β cells. Finally, we show that 4e significantly lowers blood glucose levels and increases concomitant β cell survival and number in a streptozotocin-induced diabetic mouse model. Identification of small molecule inhibitors of CHOP expression that prevent ER stress-induced β cell dysfunction and death may provide a new modality for the treatment of diabetes.
authors.affiliation: Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, United States.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Duan
authors.affiliation: Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, United States.
authors.forename: Daleep
authors.initials: D
authors.lastname: Arora
authors.affiliation: Department of Medicine, Division of Endocrinology, Department of Physiology, Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center, 941 Stanton L. Young Blvd., Oklahoma City, OK 73104, United States; Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, United States.
authors.forename: Hendra
authors.initials: H
authors.lastname: Setiadi
authors.affiliation: Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, United States.
authors.forename: Depeng
authors.initials: D
authors.lastname: Xu
authors.affiliation: Aging and Metabolism Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, United States.
authors.forename: Hui-Ying
authors.initials: HY
authors.lastname: Lim
authors.affiliation: Department of Medicine, Division of Endocrinology, Department of Physiology, Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center, 941 Stanton L. Young Blvd., Oklahoma City, OK 73104, United States; Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, United States. Electronic address: Weidong-wang@ouhsc.edu.
authors.forename: Weidong
authors.initials: W
authors.lastname: Wang
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics; D051742:Transcription Factor CHOP / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D020011:Protective Agents; D012333:RNA, Messenger; D014230:Triazoles; D051742:Transcription Factor CHOP
keywords: Anti-diabetic drug; Beta cell death; Beta cell survival; CHOP; Diabetes; ER stress