2. Academic Validation
  3. Structure-guided design, synthesis, and evaluation of guanine-derived inhibitors of the eIF4E mRNA-cap interaction

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

  • J Med Chem. 2012 Apr 26;55(8):3837-51. doi: 10.1021/jm300037x.
Xiaoqi Chen 1,  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
Affiliations

Affiliation

  • 1 Department of Chemistry Research & Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, USA. xiaoqic@amgen.com
PMID: 22458568 DOI: 10.1021/jm300037x
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.

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