Covalent Lipid Pocket Ligands Targeting p38 alpha MAPK Mutants

摘要

A chemical genetic approach is presented to covalently target a unique lipid binding pocket in the protein kinase p38 alpha, whose function is not yet known. Based on a series of cocrystal structures, a library of 2-arylquinazolines that were decorated with electrophiles were designed and synthesized to covalently target tailored p38 alpha mutants containing artificially introduced cysteine residues. Matching protein-ligand pairs were identified by MS analysis and further validated by MS/MS studies and protein crystallography. The covalent ligands that emerged from this approach showed excellent selectivity towards a single p38 alpha mutant and will be applicable as suitable probes in future studies of biological systems to dissect the function of the lipid pocket by means of pharmacological perturbations.