Targeting a key protein-protein interaction surface on mitogen-activated protein kinases by a precision-guided warhead scaffold.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
04 Oct 2024
04 Oct 2024
Historique:
received:
22
08
2023
accepted:
22
08
2024
medline:
5
10
2024
pubmed:
5
10
2024
entrez:
4
10
2024
Statut:
epublish
Résumé
For mitogen-activated protein kinases (MAPKs) a shallow surface-distinct from the substrate binding pocket-called the D(ocking)-groove governs partner protein binding. Screening of broad range of Michael acceptor compounds identified a double-activated, sterically crowded cyclohexenone moiety as a promising scaffold. We show that compounds bearing this structurally complex chiral warhead are able to target the conserved MAPK D-groove cysteine via reversible covalent modification and interfere with the protein-protein interactions of MAPKs. The electronic and steric properties of the Michael acceptor can be tailored via different substitution patterns. The inversion of the chiral center of the warhead can reroute chemical bond formation with the targeted cysteine towards the neighboring, but less nucleophilic histidine. Compounds bind to the shallow MAPK D-groove with low micromolar affinity in vitro and perturb MAPK signaling networks in the cell. This class of chiral, cyclic and enhanced 3D shaped Michael acceptor scaffolds offers an alternative to conventional ATP-competitive drugs modulating MAPK signaling pathways.
Identifiants
pubmed: 39366929
doi: 10.1038/s41467-024-52574-1
pii: 10.1038/s41467-024-52574-1
doi:
Substances chimiques
Mitogen-Activated Protein Kinases
EC 2.7.11.24
Protein Kinase Inhibitors
0
Cysteine
K848JZ4886
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
8607Informations de copyright
© 2024. The Author(s).
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