Fiche publication
Date publication
octobre 2024
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GOGL Gergo
Tous les auteurs :
Póti ÁL, Bálint D, Alexa A, Sok P, Ozsváth K, Albert K, Turczel G, Magyari S, Ember O, Papp K, Király SB, Imre T, Németh K, Kurtán T, Gógl G, Varga S, Soós T, Reményi A
Lien Pubmed
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.
Mots clés
Mitogen-Activated Protein Kinases, metabolism, Humans, Protein Binding, Protein Kinase Inhibitors, pharmacology, MAP Kinase Signaling System, drug effects, Binding Sites, Cysteine, metabolism, Models, Molecular
Référence
Nat Commun. 2024 10 4;15(1):8607
