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

Affiliations
  • 1Biomolecular Interaction Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Budapest, Hungary.
  • 2Doctoral School of Biology, Eötvös Loránd University, Budapest, Hungary.
  • 3Organocatalysis Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Budapest, Hungary.
  • 4Hevesy György PhD School of Chemistry, Eötvös Loránd University, Budapest, Hungary.
  • 5NMR Research Laboratory, Centre for Structural Science, Research Centre for Natural Sciences, Budapest, Hungary.
  • 6Department of Organic Chemistry, University of Debrecen, Debrecen, Hungary.
  • 7MS Metabolomic Research Laboratory, Centre for Structural Science, Research Centre for Natural Sciences, Budapest, Hungary.
  • 8Organocatalysis Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Budapest, Hungary. soos.tibor@ttk.hu.
  • 9Biomolecular Interaction Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Budapest, Hungary. remenyi.attila@ttk.hu.

Published on:

October 4, 2024

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.

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