A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment.
Fiche publication
Date publication
mai 2023
Journal
iScience
Auteurs
Membres identifiés du Cancéropôle Est :
Dr NEGRONI Luc
Tous les auteurs :
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
Lien Pubmed
Résumé
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 overcome 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 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 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.
Mots clés
Biological sciences, Medicine, Molecular neuroscience, Neuroscience
Référence
iScience. 2023 05 19;26(5):106687