iScience
Volume 26, Issue 5, 19 May 2023, 106687
Journal home page for iScience

Article
A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment

https://doi.org/10.1016/j.isci.2023.106687Get rights and content
Under a Creative Commons license
open access

Highlights

  • In silico screening yields a structurally new and brain-permeable IRE1 inhibitor

  • Co-treatment with temozolomide prevents glioblastoma relapses in mice

  • Validation of IRE1 as a therapeutic target for adjuvant treatment in glioblastoma

Summary

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.

Subject areas

Medicine
Biological sciences
Neuroscience
Molecular neuroscience

Data and code availability

  • The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository and is publicly available. Accession numbers are listed in the key resources table, Deposited data section.

  • No original code was generated in this study.

  • Any additional information required to reanalyse the data reported in this paper is available from the lead contact upon request.

Cited by (0)

8

These authors contributed equally

9

These authors contributed equally

10

Lead contact