PXD026908

PXD026908 is an original dataset announced via ProteomeXchange.

Title	A novel blood brain barrier-permeable IRE1 inhibitor prevents Glioblastoma relapse in mice
Description	Inositol Requiring Enzyme 1 (IRE1) is a bifunctional serine/threonine kinase and endoribonuclease that is a major mediator of the Unfolded Protein Response (UPR) during endoplasmic reticulum (ER) stress. Tumor cells experience ER stress due to adverse environmental cues such as hypoxia or nutrient shortage and high metabolic/protein folding demand. To cope with those stresses, cancer cells utilize IRE1 signaling as an adaptive mechanism. Here we report the discovery of novel family of compounds as IRE1 inhibitors identified through a structural exploration of the IRE1 kinase domain. All the inhibitors were tested for their ability to sensitize glioblastoma (GBM) cells to chemotherapy. We show that all molecules identified inhibit IRE1 signaling and sensitize glioblastoma cells to the standard of care chemotherapy temozolomide (TMZ). From these inhibitors we selected one that was able to cross the Brain Blood Barrier (BBB) and evaluated its capacity to inhibit tumor growth and avoid relapse in vivo. These results support the attractiveness of IRE1 as an adjuvant therapeutic target in GBM; a common and wholly fatal diagnosis. In addition, they provide scope for quickly testing IRE1 inhibitor suitability in GBM as adjuvant therapy due to their current status for clinical use.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_09:03:12.971.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Luc Negroni
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2021-06-24 06:54:39	ID requested
1	2023-07-20 11:16:35	announced
⏵ 2	2023-11-14 09:03:22	announced	2023-11-14: Updated project metadata.

Pelizzari-Raymundo D, Doultsinos D, Pineau R, Sauzay C, Koutsandreas T, Langlais T, Carlesso A, Gkotsi E, Negroni L, Avril T, Chatziioannou A, Chevet E, Eriksson LA, Guillory X, A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment. iScience, 26(5):106687(2023) [pubmed]

submitter keyword: IRE1, glioblastoma, Unfolded Protein Response, Inhibitors,Endoplasmic Reticulum

Eric Chevet
contact affiliation	INSERM U1242, Université de Rennes, Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France.
contact email	eric.chevet@inserm.fr
lab head
Luc Negroni
contact affiliation	CNRS
contact email	luc.negroni@igbmc.fr
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/07/PXD026908

PRIDE project URI

• PRIDE
  1. PXD026908
     1. Label: PRIDE project
     2. Name: A novel blood brain barrier-permeable IRE1 inhibitor prevents Glioblastoma relapse in mice