A novel blood brain barrier-permeable IRE1 kinase inhibitor sensitizes glioblastoma to chemotherapy in mice.

Inositol Requiring Enzyme 1 (IRE1) is a bifunctional serine/threonine kinase and endoribonuclease. It is a major mediator of the Unfolded Protein Response (UPR), which is activated during endoplasmic reticulum (ER) stress. Tumor cells experience ER stress due to adverse microenvironmental cues such as hypoxia or nutrient shortage and high metabolic/protein folding demand. To cope with those stresses, cancer cells utilize IRE1 signaling as an adaptive mechanism. Here we report the discovery of novel IRE1 inhibitors identified through a structural exploration of the IRE1 kinase domain. We first characterized these candidates in vitro and in cellular models. We showed that all molecules inhibit IRE1 signaling and sensitize glioblastoma cells to the standard chemotherapeutic temozolomide (TMZ). From these inhibitors, we retained a Blood-Brain Barrier (BBB) permeable molecule (Z4P) and demonstrated its ability to inhibit Glioblastoma (GB) growth and to prevent relapse in vivo when administered together with TMZ. These results support the attractiveness of IRE1 as an adjuvant therapeutic target in GB. We thus satisfy an unmet need for targeted, non-toxic, IRE1 inhibitors as adjuvant therapeutic agents against GB.