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Title: A High-Throughput Screen Identifies 2,9-Diazaspiro[5.5]Undecanes as Inducers of the Endoplasmic Reticulum Stress Response with Cytotoxic Activity in 3D Glioma Cell Models
Authors: Martinez, Natalia J.
Rai, Ganesha
Yasgar, Adam
Lea, Wendy A.
Sun, Hongmao
Wang, Yuhong
Luci, Diane K.
Yang, Shyh-Ming
Nishihara, Kana
Takeda, Shunichi
Sagor, Mohiuddin
Earnshaw, Irina
Okada, Tetsuya  kyouindb  KAKEN_id
Mori, Kazutoshi
Wilson, Kelli
Riggins, Gregory J.
Xia, Menghang
Grimaldi, Maurizio
Jadhav, Ajit
Maloney, David J.
Simeonov, Anton
Author's alias: 森, 和俊
Issue Date: 29-Aug-2016
Publisher: Public Library of Science
Journal title: PLOS ONE
Volume: 11
Issue: 8
Thesis number: e0161486
Abstract: The endoplasmic reticulum (ER) is involved in Ca2+ signaling and protein folding. ER Ca2+ depletion and accumulation of unfolded proteins activate the molecular chaperone GRP78 (glucose-regulated protein 78) which in turn triggers the ER stress response (ERSR) pathway aimed to restore ER homeostasis. Failure to adapt to stress, however, results in apoptosis. We and others have shown that malignant cells are more susceptible to ERSR-induced apoptosis than their normal counterparts, implicating the ERSR as a potential target for cancer therapeutics. Predicated on these findings, we developed an assay that uses a GRP78 biosensor to identify small molecule activators of ERSR in glioma cells. We performed a quantitative high-throughput screen (qHTS) against a collection of ~425, 000 compounds and a comprehensive panel of orthogonal secondary assays was formulated for stringent compound validation. We identified novel activators of ERSR, including a compound with a 2, 9-diazaspiro[5.5]undecane core, which depletes intracellular Ca2+ stores and induces apoptosis-mediated cell death in several cancer cell lines, including patient-derived and 3D cultures of glioma cells. This study demonstrates that our screening platform enables the identification and profiling of ERSR inducers with cytotoxic activity and advocates for characterization of these compound in in vivo models.
Rights: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
DOI(Published Version): 10.1371/journal.pone.0161486
PubMed ID: 27570969
Appears in Collections:Journal Articles

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