Targeting a key protein-protein interaction surface on mitogen-activated protein kinases by a precision-guided warhead scaffold

• Published in: Nature communications 2024-10, Vol.15 (1), p.8607-22, Article 8607
• Main Authors: Póti, Ádám Levente, Bálint, Dániel, Alexa, Anita, Sok, Péter, Ozsváth, Kristóf, Albert, Krisztián, Turczel, Gábor, Magyari, Sarolt, Ember, Orsolya, Papp, Kinga, Király, Sándor Balázs, Imre, Tímea, Németh, Krisztina, Kurtán, Tibor, Gógl, Gergő, Varga, Szilárd, Soós, Tibor, Reményi, Attila
• Format: Article
• Language: English
• Subjects: 101/6; 631/45/275; 631/535/1266; 631/92/609; 82/103; 82/58; 96/95; 96/98; Binding; Binding Sites; Chemical bonds; Chemical compounds; Covalent bonds; Cysteine; Cysteine - chemistry; Cysteine - metabolism; Drug interaction; Grooves; Histidine; Humanities and Social Sciences; Humans; Kinases; MAP kinase; MAP Kinase Signaling System - drug effects; Mitogen-Activated Protein Kinases - metabolism; Models, Molecular; multidisciplinary; Protein Binding; Protein interaction; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proteins; Scaffolds; Science; Science (multidisciplinary); Substrates; Warheads
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52574-1

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. Póti et al developed cyclic, tuneable and chiral warheads against the protein-protein interaction surface of mitogen-activated protein kinases, which form a reversible covalent bond with nucleophilic surface residues to modulate cellular signaling networks.