Peptidomimetic-based identification of FDA approved compounds inhibiting IRE1 activity - Fondation pour la Recherche Médicale Accéder directement au contenu
Article Dans Une Revue FEBS Journal Année : 2021

Peptidomimetic-based identification of FDA approved compounds inhibiting IRE1 activity

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 optimization 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).

Domaines

Cancer
Fichier principal
Vignette du fichier
Doultsinos - Peptidomimetic‐based identification of FDA‐approved compounds inhibiting IRE1.pdf (2.17 Mo) Télécharger le fichier
Origine : Publication financée par une institution

Dates et versions

hal-02862262 , version 1 (23-01-2023)

Licence

Paternité

Identifiants

Citer

Dimitrios Doultsinos, Antonio Carlesso, Chetan Chintha, James C Paton, Adrienne W Paton, et al.. Peptidomimetic-based identification of FDA approved compounds inhibiting IRE1 activity. FEBS Journal, 2021, 288 (3), pp.945-960. ⟨10.1111/febs.15372⟩. ⟨hal-02862262⟩
95 Consultations
56 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More