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
  • 1. Department of Chemistry Research & Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, USA. [email protected]
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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