Discovery of Lysine-Targeted eIF4E Inhibitors through Covalent Docking

• DOI: 10.1021/jacs.9b10377
• Publication Date: 2020-02-27T21:36:30Z
• Authors: Xiaobo Wan; Tangpo Yang; Adolfo Cuesta; Xiaming Pang; Trent E. Balius; John J. Irwin; Brian K. Shoichet; Jack Taunton
• Keywords: 0301 basic medicine; Sulfonamides; Binding Sites; Lysine; General Chemistry; 3. Good health; Molecular Docking Simulation; Medicinal and Biomolecular Chemistry; 03 medical and health sciences; Rare Diseases; Engineering; Eukaryotic Initiation Factor-4E; HEK293 Cells; Chemical sciences; Chemical Sciences; Drug Discovery; Humans; Cancer; Protein Binding

Eukaryotic translation initiation factor 4E (eIF4E) binds the m7GTP cap structure at the 5'-end of mRNAs, stimulating the translation of proteins implicated in cancer cell growth and metastasis. eIF4E is a notoriously challenging target, and most of the reported inhibitors are negatively charged guanine analogues with negligible cell permeability. To overcome these challenges, we envisioned a covalent targeting strategy. As there are no cysteines near the eIF4E cap binding site, we developed a covalent docking approach focused on lysine. Taking advantage of a "make-on-demand" virtual library, we used covalent docking to identify arylsulfonyl fluorides that target a noncatalytic lysine (Lys162) in eIF4E. Guided by cocrystal structures, we elaborated arylsulfonyl fluoride 2 to 12, which to our knowledge is the first covalent eIF4E inhibitor with cellular activity. In addition to providing a new tool for acutely inactivating eIF4E in cells, our computational approach may offer a general strategy for developing selective lysine-targeted covalent ligands.