title: Benzodiazepinone derivatives protect against endoplasmic reticulum stress-mediated cell death in human neuronal cell lines.
abstract: Endoplasmic reticulum (ER) stress causes neuronal dysfunction followed by cell death and is recognized as a feature of many neurodegenerative diseases. Using a phenotypic screen, we recently identified benzodiazepinone derivatives that reduce ER stress-mediated apoptosis in a rat neuronal progenitor cell line (CSM14.1). Herein we describe how structure-activity relationship (SAR) studies around these screening hits led to compounds that display robust cytoprotective activity against thapsigargin-induced ER stress in SH-SY5Y and H4 human neuronal cell lines. We demonstrate that the most potent of these derivatives, compound 4hh, inhibits the activation of p38 MAP kinase (p38) and c-Jun N-terminal kinase (JNK), protein kinases that are downstream signal effectors of the unfolded protein response (UPR). Compound 4hh specifically protects against thapsigargin-induced cell death and displays no protection against other insults known to induce cellular stress or activate p38. However, compound 4hh provides moderate inhibition of p38 activity stimulated by compounds that disrupt calcium homeostasis. Our data indicate that probe compound 4hh is a valuable small molecule tool that can be used to investigate the effects of ER stress on human neurons. This approach may provide the basis for the future development of therapeutics for the treatment of neurodegenerative diseases.
authors.affiliation: †Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, and ‡Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Haixia
authors.initials: H
authors.lastname: Zou
authors.affiliation: †Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, and ‡Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Allison S
authors.initials: AS
authors.lastname: Limpert
authors.affiliation: †Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, and ‡Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Jiwen
authors.initials: J
authors.lastname: Zou
authors.affiliation: †Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, and ‡Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Dembo
authors.affiliation: †Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, and ‡Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Pooi-San
authors.initials: PS
authors.lastname: Lee
authors.affiliation: †Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, and ‡Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Grant
authors.affiliation: †Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, and ‡Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Ardecky
authors.affiliation: †Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, and ‡Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Pinkerton
authors.affiliation: †Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, and ‡Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Gavin K
authors.initials: GK
authors.lastname: Magnuson
authors.affiliation: †Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, and ‡Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Goldman
authors.affiliation: †Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, and ‡Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Juan
authors.initials: J
authors.lastname: Rong
authors.affiliation: †Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, and ‡Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Teriete
authors.affiliation: †Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, and ‡Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Sheffler
authors.affiliation: †Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, and ‡Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.affiliation: †Cell Death and Survival Networks Research Program, NCI-Designated Cancer Center, and ‡Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Nicholas D P
authors.initials: ND
authors.lastname: Cosford
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000737:chemistry* / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000633:toxicity; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D019284:Thapsigargin / Q000737:chemistry / Q000633:toxicity
chemical_list: C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D001570:Benzodiazepinones; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007976:Leupeptins; D015759:Ionomycin; D019284:Thapsigargin; D009828:Oleanolic Acid; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D002118:Calcium
keywords: Benzodiazepinone; ER stress; calcium homeostasis; neurodegeneration; p38 MAPK; thapsigargin