A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment

Diana Pelizzari Raymundo (1) , Dimitrios Doultsinos (1) , Raphaël Pineau (1) , Chloé Sauzay (1) , Thodoris Koutsandreas (2) , Timothy Langlais (3) , Antonio Carlesso (4) , Elena Gkotsi (2) , Luc Negroni (5, 6) , Tony Avril (1) , Aristotelis Chatziioannou (2) , Eric Chevet (1) , Leif A. Eriksson (4) , Xavier Guillory (1, 3)

1 OSS - Oncogenesis, Stress, Signaling
2 BRFAA - Biomedical Research Foundation of the Academy of Athens
3 ISCR - Institut des Sciences Chimiques de Rennes
4 GU - Göteborgs Universitet = University of Gothenburg
5 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
6 Inserm U964 - CNRS UMR7104 - IGBMC - Centre for Integrative Biology - CBI

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 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.

Mots clés: Biological sciences; Medicine; Molecular neuroscience; Neuroscience

Domaines: Chimie thérapeutique

Diana Pelizzari Raymundo, Dimitrios Doultsinos, Raphaël Pineau, Chloé Sauzay, Thodoris Koutsandreas, et al.. A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment. iScience, 2023, 26 (5), pp.106687. ⟨10.1016/j.isci.2023.106687⟩. ⟨hal-04120068⟩