Peptidomimetic-based identification of FDA-approved compounds inhibiting IRE1 activity.
Cefoperazone
/ chemistry
Cell Line, Tumor
Drug Approval
Endoplasmic Reticulum Stress
/ drug effects
Endoribonucleases
/ antagonists & inhibitors
Enzyme Inhibitors
/ chemistry
Humans
Leucovorin
/ chemistry
Methotrexate
/ chemistry
Molecular Structure
Peptidomimetics
/ chemistry
Protein Binding
Protein Domains
Protein Serine-Threonine Kinases
/ antagonists & inhibitors
Signal Transduction
/ drug effects
Unfolded Protein Response
/ drug effects
United States
United States Food and Drug Administration
Vidarabine Phosphate
/ analogs & derivatives
IRE1
endoplasmic reticulum
glioblastoma
inhibitors
unfolded protein response
Journal
The FEBS journal
ISSN: 1742-4658
Titre abrégé: FEBS J
Pays: England
ID NLM: 101229646
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
19
12
2019
revised:
06
04
2020
accepted:
19
05
2020
pubmed:
24
5
2020
medline:
27
7
2021
entrez:
24
5
2020
Statut:
ppublish
Résumé
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).
Substances chimiques
Enzyme Inhibitors
0
Peptidomimetics
0
Vidarabine Phosphate
106XV160TZ
fludarabine phosphate
1X9VK9O1SC
Cefoperazone
7U75I1278D
ERN1 protein, human
EC 2.7.11.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
Endoribonucleases
EC 3.1.-
Leucovorin
Q573I9DVLP
Methotrexate
YL5FZ2Y5U1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
945-960Informations de copyright
© 2020 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
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