The eukaryotic translation initiation factor 4E (eIF4E) is a protein which binds to mRNA and stimulates its translation. It is frequently overexpressed in human cancers, with expression positively correlated to cancer progression 214 and drives cellular transformation, tumorigenesis, and metastatic progression in experimental models. Yet, despite the apparent attractiveness of targeting eIF4E (and the eIF4F complex), until recently there has been little to no development of eIF4E-specific therapies. Despite lacking a cysteine residue in the vicinity of the eIF4E cap binding site, a proximal lysine residue in eIF4E (Lys162, which interacts with the β-phosphate of the cap) was hypothesized/considered as a potential site for covalent attachment. Using a virtual docking approach, a library of approximately 88,000 arylsulfonyl fluorides was screened for candidates that could interact with Lys162 and bind within the eIF4E cap binding pocket. Based on the results of in silico screening, two viable compounds were identified which were further optimized to take advantage of a deep lipophilic pocket close to the cap binding site. Following structural optimization, an aminoquinazolinone-substituted arylsulfonyl fluoride was identified and used in cell-based assays to inhibit cap binding by eIF4E and suppress cap-dependent translation in cells.