Benzoxaboroles are structurally unique binders of eukaryotic translation initiation factor 4E

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Molecular Biology

Background:

• Benzoxaboroles possess unique reactivity and protein-binding properties valuable for drug discovery.
• Despite their potential, benzoxaboroles are underrepresented in current drug discovery efforts and fragment screening libraries.
• Targeting eukaryotic translation initiation factor 4E (eIF4E) is a significant challenge in developing small molecule therapeutics.

Purpose of the Study:

• To synthesize benzoxaborole derivatives with a diazirine/alkyne tag for in-cell photoaffinity labeling (PAL).
• To investigate the interaction of novel benzoxaboroles with eukaryotic translation initiation factor 4E (eIF4E).
• To explore the potential of benzoxaboroles as ligands for the challenging eIF4E target.

Main Methods:

• Synthesis of a focused library of benzoxaboroles featuring a diazirine/alkyne moiety.
• In-cell photoaffinity labeling (PAL) experiments to identify protein targets.
• Biochemical assays to determine binding affinity and stereoselectivity.
• Site of labeling studies to map the interaction site.
• In silico modeling to elucidate binding interactions.

Main Results:

• A subset of synthesized benzoxaboroles demonstrated high selectivity for eukaryotic translation initiation factor 4E (eIF4E).
• The binding interaction between benzoxaboroles and eIF4E was found to be stereoselective.
• The benzoxaborole interaction competed with the 7-methylguanosine mRNA cap.
• Labeling experiments confirmed that benzoxaboroles bind within the cap binding pocket of eIF4E.
• Computational modeling indicated key hydrogen bonding interactions driving affinity.

Conclusions:

• Benzoxaboroles can effectively target the eIF4E cap binding pocket.
• The observed stereoselective binding and competition with mRNA cap highlight a promising mechanism for eIF4E inhibition.
• These findings establish benzoxaboroles as a viable scaffold for developing novel therapeutics against eIF4E.