Inhibition of translation initiation represents a novel mechanism-based approach for developing more effective and safer anti-cancer drugs. High throughput screening of a diversity chemical library led to the discovery of 4EGI-1, a thiazol-2-yl hydrazone, as an inhibitor of eIF4E/eIF4G protein-protein interaction and consequently a preferential inhibitor of cap-dependent translation of weak mRNAs. 4EGI-1 inhibits tumor growth in animal models of human cancer. Combination of structural studies of eIF4E--4EGI-1 complex with NMR and molecular docking suggested hydrophobic interactions between the small molecule and a hydrophobic hot spot on eIF4E located at the interface between eIF4E and eIF4G. Structure-activity relationship studies identified the pharmacophore essential for activity and led to the development of KY-615, KY-383, and KY-689 which display 4-fold higher binding affinity to eIF4E than 4EGI-1, the parent 4-substituted-thiazol-2-yl hydrazone. Taken together, these results represent the first step toward hit-to-lead optimization.

Identification of the pharmacophore of 4EGI-1, an inhibitor of translation initiation with anti-cancer activity

240th National Meeting (2010)

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