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

Ádám Levente Póti, Dániel Bálint, Anita Alexa, Péter Sok, Kristóf Ozsváth, Krisztián Albert, Gábor Turczel, Sarolt Magyari, Orsolya Ember, Kinga Papp, Sándor Balázs Király, Tímea Imre, Krisztina Németh, Tibor Kurtán, Gergő Gógl, Szilárd Varga, Tibor Soós () and Attila Reményi ()
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Ádám Levente Póti: Research Centre for Natural Sciences
Dániel Bálint: Research Centre for Natural Sciences
Anita Alexa: Research Centre for Natural Sciences
Péter Sok: Research Centre for Natural Sciences
Kristóf Ozsváth: Research Centre for Natural Sciences
Krisztián Albert: Research Centre for Natural Sciences
Gábor Turczel: Research Centre for Natural Sciences
Sarolt Magyari: Research Centre for Natural Sciences
Orsolya Ember: Research Centre for Natural Sciences
Kinga Papp: Research Centre for Natural Sciences
Sándor Balázs Király: University of Debrecen
Tímea Imre: Research Centre for Natural Sciences
Krisztina Németh: Research Centre for Natural Sciences
Tibor Kurtán: University of Debrecen
Gergő Gógl: Research Centre for Natural Sciences
Szilárd Varga: Research Centre for Natural Sciences
Tibor Soós: Research Centre for Natural Sciences
Attila Reményi: Research Centre for Natural Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-52574-1

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