Abstract 4462: Covalent inhibition of eIF4E: A computational approach

Abstract Covalent docking has emerged as a promising strategy for targeting challenging protein residues. Specifically, lysine residues, which are often overlooked due to their lower nucleophilicity compared to cysteines, have shown potential in the development of covalent inhibitors for eukaryotic translation initiation factor 4E (eIF4E), a critical regulator of protein synthesis implicated in breast cancers. Leveraging aryl sulfonyl fluorides, recent studies had successfully docked to K162 within eIF4E and shown reduced protein activity, but the molecules had faced significant specificity and instability. In this study, I improved the molecules in the following aspects: specificity and stability. Regarding specificity, I found additional lysine residues, such as K106 and K108, as promising targets for covalent inhibition through structural analyses of eIF4E. I also designed bivalent molecules that covalently bind to both lysine residues simultaneously. This bivalent binding increases the specificity as there are only two regions of two lysine residues in three amino acids, whereas there are a total of 15 lysine residues. The differences in binding affinity and docking score between the bivalent and control groups were insignificant, suggesting that the potency of the bivalent molecule didn’t drop. Finally, through molecular dynamic simulations, I verified that there is conformational changes at the cap-binding site after covalent inhibition, demonstrating the biological efficacy of the drug molecules. Citation Format: Xingchuan Ma. Covalent inhibition of eIF4E: A computational approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4462.