Document Report Card

ID: ALA2046428

Journal: J Med Chem

Title: Structure-guided design, synthesis, and evaluation of guanine-derived inhibitors of the eIF4E mRNA-cap interaction.

Authors: Chen X, Kopecky DJ, Mihalic J, Jeffries S, Min X, Heath J, Deignan J, Lai S, Fu Z, Guimaraes C, Shen S, Li S, Johnstone S, Thibault S, Xu H, Cardozo M, Shen W, Walker N, Kayser F, Wang Z.

Abstract: The eukaryotic initiation factor 4E (eIF4E) plays a central role in the initiation of gene translation and subsequent protein synthesis by binding the 5' terminal mRNA cap structure. We designed and synthesized a series of novel compounds that display potent binding affinity against eIF4E despite their lack of a ribose moiety, phosphate, and positive charge as present in m7-GMP. The biochemical activity of compound 33 is 95 nM for eIF4E in an SPA binding assay. More importantly, the compound has an IC(50) of 2.5 μM for inhibiting cap-dependent mRNA translation in a rabbit reticular cell extract assay (RRL-IVT). This series of potent, truncated analogues could serve as a promising new starting point toward the design of neutral eIF4E inhibitors with physicochemical properties suitable for cellular activity assessment.

CiteXplore: 22458568

DOI: 10.1021/jm300037x