Development and delivery of eukaryotic initiation factor 4E (eIF4E) antagonists as potential anticancer therapeutics

Eukaryotic initiation factor eIF4E, the rate limiting factor in cap-dependent translation initiation, is considered to be a therapeutic target for various cancers. The initiation of eukaryotic translation depends on the binding of eIF4E to 7'-methylated guanosine capped mRNA. 7-benzyl guanosine monophosphate (Bn7GMP) showed a 10-fold increase (Kd = 1.32 +/- 0.062 muM) compared to 7-methyl guanosine monophosphate (Me7GMP). A combinatorial docking of Bn7GMP analogs was conducted using CombiGlide from SchrodingerRTM, which guided the synthesis of a library of 7N-substituted benzyl GMP analogues. After determining their biological activities, three-dimensional quantitative structure-activity relationship (3D-QSAR) models have been derived with comparative molecular filed analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) using these analogs as the training set. The models could offer new insights into binding modes of eIF4E with cap analogs and were presented as a valuable tool to study ligand-receptor interactions.;Our next goal is to improve the cell permeability of eIF4E antagonists using a prodrug strategy. We synthesized the corresponding phosphoramidate 4Ei-1 and carry out its in vitro metabolism studies in breast cancer MDA-MB-231 cells using HPLC-MS/MS. Although 4Ei-1 did not cause obvious cytotoxicity in breast cancer cells, our cell proliferation studies suggested that 4Ei-1 was able to chemosensitize MCF-7 cells to the treatment with the commonly used anticancer agent 5-FU, probably through the regulation of thymidylate synthase. Overall, our work further proves eIF4E as a therapeutic target for chemotherapy and shows the potential use of eIF4E antagonist in the combination with other anticancer agents, for the purpose of chemosensitization or even overcoming drug resistance.