Disclosed here are a series of novel cap-competitive covalent inhibitors of eukaryotic initiation factor 4E (eIF4E) that display potent mass modification, efficacy and target occupancy of eIF4E compared to their non-covalent counterparts 7-methylguanosine monophosphate (m7-GMP) and compound <b>1</b>. eIF4E plays a central role in gene translation and protein synthesis in eukaryotic cells and is associated with the proliferation and growth of tumors, due to the observed over-expression of eIF4E in multiple tumor types. Through the use of modeling, x-ray crystallography and exploratory covalent lysine warhead chemistry, we were able to structurally modify compound <b>1</b> to optimize the interaction between lysine 162 and various warheads, while also attempting to improve potency.

eIF4E mRNA-cap-competitive covalent inhibitors: Design, synthesis and effectiveness

2019 Fall National Meeting

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