| Summary: | Inositol-requiring enzyme 1 (IRE1) is a bifunctional serine/threonine kinase
and endoribonuclease that is a major mediator of the unfolded protein
response (UPR) during endoplasmic reticulum (ER) stress. Tumour cells
experience ER stress due to adverse environmental cues such as hypoxia or
nutrient shortage and high metabolic/protein-folding demand. To cope
with those stresses, cancer cells utilise IRE1 signalling as an adaptive mechanism. Here, we report the discovery of the FDA-approved compounds
methotrexate, cefoperazone, folinic acid and fludarabine phosphate as
IRE1 inhibitors. These were identified through a structural exploration of
the IRE1 kinase domain using IRE1 peptide fragment docking and further
optimisation and pharmacophore development. The inhibitors were verified
to have an impact on IRE1 activity in vitro and were tested for their ability
to sensitise human cell models of glioblastoma multiforme (GBM) to
chemotherapy. We show that all molecules identified sensitise glioblastoma
cells to the standard-of-care chemotherapy temozolomide (TMZ).
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