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

Dimitrios Doultsinos; Antonio Carlesso; Chetan Chintha; James C Paton; Adrienne W Paton; Afshin Samali; Eric Chevet; Leif A Eriksson

doi:10.1111/febs.15372

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

FEBS J. 2021 Feb;288(3):945-960. doi: 10.1111/febs.15372. Epub 2020 Jun 11.

Authors

Dimitrios Doultsinos^{1

2}, Antonio Carlesso³, Chetan Chintha⁴, James C Paton⁵, Adrienne W Paton⁵, Afshin Samali⁴, Eric Chevet^{1

2}, Leif A Eriksson³

Affiliations

¹ Proteostasis & Cancer Team INSERM U1242 'Chemistry, Oncogenesis Stress Signaling', Université de Rennes, France.
² Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France.
³ Department of Chemistry and Molecular Biology, University of Gothenburg, Sweden.
⁴ Apoptosis Research Centre, School of Natural Sciences, NUI Galway, Ireland.
⁵ Research Centre for Infectious Diseases, Department of Molecular and Biomedical Science, University of Adelaide, SA, Australia.

PMID: 32446294
DOI: 10.1111/febs.15372

Abstract

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).

Keywords: IRE1; endoplasmic reticulum; glioblastoma; inhibitors; unfolded protein response.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cefoperazone / chemistry
Cefoperazone / metabolism
Cefoperazone / pharmacology
Cell Line, Tumor
Drug Approval
Endoplasmic Reticulum Stress / drug effects*
Endoribonucleases / antagonists & inhibitors*
Endoribonucleases / chemistry
Endoribonucleases / metabolism
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology
Humans
Leucovorin / chemistry
Leucovorin / metabolism
Leucovorin / pharmacology
Methotrexate / chemistry
Methotrexate / metabolism
Methotrexate / pharmacology
Molecular Structure
Peptidomimetics / chemistry
Peptidomimetics / metabolism
Peptidomimetics / pharmacology*
Protein Binding
Protein Domains
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / chemistry
Protein Serine-Threonine Kinases / metabolism
Signal Transduction / drug effects*
Unfolded Protein Response / drug effects*
United States
United States Food and Drug Administration
Vidarabine Phosphate / analogs & derivatives
Vidarabine Phosphate / chemistry
Vidarabine Phosphate / metabolism
Vidarabine Phosphate / pharmacology

Substances

Enzyme Inhibitors
Peptidomimetics
Vidarabine Phosphate
fludarabine phosphate
Cefoperazone
ERN1 protein, human
Protein Serine-Threonine Kinases
Endoribonucleases
Leucovorin
Methotrexate