A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment

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.

Graphical abstract

Highlights

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

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  Co-treatment with temozolomide prevents glioblastoma relapses in mice

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

Abstract

Medicine; Biological sciences; Neuroscience; Molecular neuroscience