Structure–activity relationship study of 4EGI-1, small molecule eIF4E/eIF4G protein–protein interaction inhibitors

• SAR of 4EGI-1, an inhibitor of eIF4E/eIF4G interaction and of translation initiation.
• The benzyl ring prefers a combination of polar substituents (e.g. NO2 and NH2).
• The phenyl ring prefers hydrophobic substituents such as a p-phenyl.
• Gained insight on the hydrazono-E/Z-isomerization and its relevance to physical properties.

Protein–protein interactions are critical for regulating the activity of translation initiation factors and multitude of other cellular process, and form the largest block of untapped albeit most challenging targets for drug development. 4EGI-1, (E/Z)-2-(2-(4-(3,4-dichlorophenyl)thiazol-2-yl)hydrazono)-3-(2-nitrophenyl)propanoic acid, is a hit compound discovered in a screening campaign of small molecule libraries as an inhibitor of translation initiation factors eIF4E and eIF4G protein–protein interaction; it inhibits translation initiation in vitro and in vivo. A series of 4EGI-1-derived thiazol-2-yl hydrazones have been designed and synthesized in order to delineate the structural latitude and improve its binding affinity to eIF4E, and increase its potency in inhibiting the eIF4E/eIF4G interaction. Probing a wide range of substituents on both phenyl rings comprising the 3-phenylpropionic acid and 4-phenylthiazolidine moieties in the context of both E- and Z-isomers of 4EGI-1 led to analogs with enhanced binding affinity and translation initiation inhibitory activities.

Figure optionsDownload as PowerPoint slide