Peptidomimetic-based identification of FDA-approved compounds inhibiting IRE1 activity

Doultsinos, D. (author)

Carlesso, Antonio, 1990 (author): Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology

Chintha, C. (author)

Paton, J. C. (author)

Paton, A. W. (author)

Samali, A. (author)

Chevet, E. (author)

Eriksson, Leif A, 1964 (author): Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology

(creator_code:org_t)

2020-06-11
2021
English.
In: Febs Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 288:3, s. 945-960

Related links:: https://febs.onlinel...; show more...; https://gup.ub.gu.se...; https://doi.org/10.1...; show less...

Abstract Subject headings

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 activityin vitroand 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).

NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

By the author/editor: Doultsinos, D.; Carlesso, Antoni ...; Chintha, C.; Paton, J. C.; Paton, A. W.; Samali, A.; show more...; Chevet, E.; Eriksson, Leif A ...; show less...

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

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