Benzoxaboroles Are Structurally Unique Binders of Eukaryotic Translation Initiation Factor 4E

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Structural Biology

Background:

• Benzoxaboroles possess unique reactivity and protein-binding capabilities valuable for drug discovery.
• Despite their potential, benzoxaboroles are not widely utilized in drug discovery or fragment screening libraries.
• Developing novel small molecules targeting challenging protein pockets remains a key area in pharmaceutical research.

Purpose of the Study:

• To synthesize benzoxaborole derivatives with a diazirine/alkyne tag for in-cell photoaffinity labeling.
• To investigate the selectivity and binding interactions of benzoxaboroles with eukaryotic translation initiation factor 4E (eIF4E).
• To explore the potential of benzoxaboroles as inhibitors of eIF4E for therapeutic applications.

Main Methods:

• Synthesis of a benzoxaborole library featuring a diazirine/alkyne tag.
• In-cell photoaffinity labeling experiments to identify protein targets.
• Biochemical assays to determine binding affinity and selectivity for eIF4E.
• Site of labeling studies and computational modeling to elucidate binding modes.

Main Results:

• A subset of synthesized benzoxaboroles exhibited high selectivity for eukaryotic translation initiation factor 4E (eIF4E).
• The interaction between benzoxaboroles and eIF4E was stereoselective and competed with mRNA 7-methylguanosine cap binding.
• Photoaffinity labeling and modeling confirmed that benzoxaboroles bind within the eIF4E cap-binding pocket, involving key hydrogen bonding interactions.

Conclusions:

• Benzoxaboroles can be effectively functionalized for photoaffinity labeling to identify drug targets.
• The study demonstrates the potential of benzoxaboroles to selectively target and bind to the challenging eIF4E cap-binding pocket.
• These findings highlight benzoxaboroles as a promising scaffold for developing novel therapeutics, particularly for diseases involving aberrant protein synthesis regulation.