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A novel IRE1 kinase...
A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment
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Pelizzari-Raymundo, D. (author)
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Doultsinos, D. (author)
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Pineau, R. (author)
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Sauzay, C. (author)
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Koutsandreas, T. (author)
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Langlais, T. (author)
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- Carlesso, Antonio, 1990 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
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Gkotsi, E. (author)
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Negroni, L. (author)
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Avril, T. (author)
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Chatziioannou, A. (author)
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Chevet, E. (author)
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- Eriksson, Leif A, 1964 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
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Guillory, X. (author)
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(creator_code:org_t)
- 2023
- 2023
- English.
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In: iScience. - 2589-0042. ; 26:5
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
Subject headings
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- Inositol-requiring enzyme 1 (IRE1) is a major mediator of the unfolded protein response (UPR), which is activated upon endoplasmic reticulum (ER) stress. Tumor cells experience ER stress due to adverse microenvironmental cues, a stress over-come by relying on IRE1 signaling as an adaptive mechanism. Herein, we report the discovery of structurally new IRE1 inhibitors identified through the structural exploration of its kinase domain. Characterization in in vitro and in cellular models showed that they inhibit IRE1 signaling and sensitize glioblastoma (GB) cells to the standard chemotherapeutic, temozolomide (TMZ). Finally, we demonstrate that one of these inhibitors, Z4P, permeates the blood-brain barrier (BBB), inhibits GB growth, and prevents relapse in vivo when administered together with TMZ. The hit compound disclosed herein satisfies an unmet need for targeted, non-toxic IRE1 inhibitors and our results support the attractiveness of IRE1 as an adjuvant therapeutic target in GB.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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iScience
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- By the author/editor
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Pelizzari-Raymun ...
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Doultsinos, D.
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Pineau, R.
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Sauzay, C.
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Koutsandreas, T.
-
Langlais, T.
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show more...
-
Carlesso, Antoni ...
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Gkotsi, E.
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Negroni, L.
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Avril, T.
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Chatziioannou, A ...
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Chevet, E.
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Eriksson, Leif A ...
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Guillory, X.
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show less...
- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
- Articles in the publication
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iScience
- By the university
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University of Gothenburg