Proximity-induced amino-yne reaction for selective MDM4 conjugation via propargylated sulfonium

Whilst most bioorthogonal reactions focus on targeting binding-site cysteine residues, proximity-induced reactivity effect ensures that reaction also occurs at nucleophilic lysine residues. We report one example here that the propargylated-sulfonium center undergoes a nucleophilic reaction with lysine residue via proximity-induced conjugation. This propargylated-sulfonium tethered peptide resulting from a facile propargylation of thiolethers, enables amino-yne reaction at the selected lysine on MDM4 protein. This strategy represents a viable approach of lysine-targeted covalent inhibition in proximity. (C) 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.