Lysine-Targeted Covalent Inhibition of eIF4E with an Anionic Electrophile Warhead

Abstract

Covalent strategies offer a powerful route to expand the druggable proteome, yet selective lysine targeting remains difficult due to the high pKa and protonation of the amine side chain. The translation initiation factor eIF4E, an mRNA cap-binding protein that controls nuclear export and translation of oncogenic transcripts, has long been considered an undruggable RNA-binding protein. We apply an anionic electrophile strategy that converts a carboxylic acid within a reversible eIF4E ligand into a vinyl acylsulfonamide warhead, preserving salt-bridge and hydrogen bonding interactions in the cap-binding pocket and facilitating Lys162 deprotonation to enable site-specific engagement. This single-step transformation yields JL-03, a potent covalent eIF4E inhibitor with excellent stability toward biological nucleophiles, consistent with context-dependent activation of the warhead in the binding site. In cells, JL-03 achieves robust target engagement and suppresses translation of the oncogenic driver cyclin D. JL-03 reduces the viability of HOXA9-high acute myeloid leukemia cells with greater potency than reversible eIF4E inhibitors and synergizes with the menin inhibitor revumenib, demonstrating that coordinated transcriptional and translational blockade exhausts leukemic dependencies. These findings establish eIF4E as a tractable covalent target and highlight anionic electrophile installation as a generalizable strategy for lysine-directed covalent inhibitor design.