2. Academic Validation
  3. A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment

A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment

  • iScience. 2023 Apr 24;26(5):106687. doi: 10.1016/j.isci.2023.106687.
Diana Pelizzari-Raymundo 1 2,  Dimitrios Doultsinos 1 2,  Raphael Pineau 1 2,  Chloé Sauzay 1 2,  Thodoris Koutsandreas 3 4,  Timothy Langlais 5,  Antonio Carlesso 6,  Elena Gkotsi 3 4,  Luc Negroni 7,  Tony Avril 1 2,  Aristotelis Chatziioannou 3 4,  Eric Chevet 1 2,  Leif A Eriksson 6,  Xavier Guillory 1 2 5
Affiliations

Affiliations

  • 1 INSERM U1242, Université de Rennes, Rennes, France.
  • 2 Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France.
  • 3 e-NIOS PC, Kallithea-Athens, Greece.
  • 4 Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
  • 5 Univ Rennes, CNRS, ISCR - UMR 6226, 35000 Rennes, France.
  • 6 Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden.
  • 7 Proteomics platform, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)/INSERM U964/CNRS UMR 7104/Université de Strasbourg, Illkirch, France.
PMID: 37216120 DOI: 10.1016/j.isci.2023.106687
Abstract

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.

Keywords

Biological sciences; Medicine; Molecular neuroscience; Neuroscience.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-153773
    99.32%, IRE1 Inhibitor