ArticleNature communications2024
Targeting a key protein-protein interaction surface on mitogen-activated protein kinases by a precision-guided warhead scaffold.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Genetic Deletion of Cyclophilin D Results in Enhanced Hypoxia Tolerance in Mice.Cellular and molecular neurobiology · 2026Article
- Multifaceted Small Molecules as Enzyme Modulators: Cases of Drug Discovery/Repurposing Illustrating Nature's Pragmatism.BioMed research international · 2026Review
- Exploratory Covalent Docking of Michael-Acceptor Natural Products at Reactive Cysteines in Cancer Tyrosine Kinases.International journal of molecular sciences · 2025Article
- Reversible covalent c-Jun N-terminal kinase inhibitors targeting a specific cysteine by precision-guided Michael-acceptor warheads.Nature communications · 2024Article
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Authors and funding
18 authors.
Funding
No grant is acknowledged in the PubMed record.
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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Registered trials
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