Structure-Guided Design, Synthesis, and Evaluation of Guanine-Derived Inhibitors of the eIF4E mRNA–Cap Interaction

• DOI: 10.1021/jm300037x
• Publication Date: 2012-03-29T17:27:41Z
• Authors: Xiaoqi Chen; David J. Kopecky; Jeff Mihalic; Shawn Jeffries; Xiaoshan Min; Julie Heath; Jeff Deignan; SuJen Lai; Zice Fu; Cristiano Guimaraes; Shanling Shen; Shyun Li; Sheree Johnstone; Stephen Thibault; Haoda Xu; Mario Cardozo; Wang Shen; Nigel Walker; Frank Kayser; Zhulun Wang
• Keywords: EIF4E; Eukaryotic translation; Moiety

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