From PERK to RIPK1: Design, synthesis and evaluation of novel potent and selective necroptosis inhibitors.
PERK (PKR-like endoplasmic reticulum kinase)
RIPK1 inhibitor
inflammation
necroptosis
regulated cell death
type II kinase inhibitor
Journal
Frontiers in chemistry
ISSN: 2296-2646
Titre abrégé: Front Chem
Pays: Switzerland
ID NLM: 101627988
Informations de publication
Date de publication:
2023
2023
Historique:
received:
06
02
2023
accepted:
28
03
2023
medline:
24
4
2023
pubmed:
24
4
2023
entrez:
24
04
2023
Statut:
epublish
Résumé
Receptor-Interacting serine/threonine-Protein Kinase 1 (RIPK1) emerged as an important driver of inflammation and, consequently, inflammatory pathologies. The enzymatic activity of RIPK1 is known to indirectly promote inflammation by triggering cell death, in the form of apoptosis, necroptosis and pyroptosis. Small molecule Receptor-Interacting serine/threonine-Protein Kinase 1 inhibitors have therefore recently entered clinical trials for the treatment of a subset of inflammatory pathologies. We previously identified GSK2656157 (GSK'157), a supposedly specific inhibitor of protein kinase R (PKR)-like ER kinase (PERK), as a much more potent type II Receptor-Interacting serine/threonine-Protein Kinase 1 inhibitor. We now performed further structural optimisation on the GSK'157 scaffold in order to develop a novel class of more selective Receptor-Interacting serine/threonine-Protein Kinase 1 inhibitors. Based on a structure-activity relationship (SAR) reported in the literature, we anticipated that introducing a substituent on the
Identifiants
pubmed: 37090247
doi: 10.3389/fchem.2023.1160164
pii: 1160164
pmc: PMC10119423
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1160164Informations de copyright
Copyright © 2023 Scarpellini, Valembois, Goossens, Vadi, Lanthier, Klejborowska, Van Der Veken, De Winter, Bertrand and Augustyns.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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