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

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, bu

SUBMITTER: Poti AL 

PROVIDER: S-EPMC11452651 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature