Nontoxic Chemical Interdiction of the Epithelial-to-Mesenchymal Transition by Targeting Cap-Dependent Translation

Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
ACS Chemical Biology (Impact Factor: 5.33). 05/2009; 4(5):367-77. DOI: 10.1021/cb9000475
Source: PubMed


Normal growth and development depends upon high fidelity regulation of cap-dependent translation initiation, a process that is usurped and redirected in cancer to mediate acquisition of malignant properties. The epithelial-to-mesenchymal transition (EMT) is a key translationally regulated step in the development of epithelial cancers and pathological tissue fibrosis. To date, no compounds targeting EMT have been developed. Here we report the synthesis of a novel class of histidine triad nucleotide binding protein (HINT)-dependent pronucleotides that interdict EMT by negatively regulating the association of eIF4E with the mRNA cap. Compound eIF4E inhibitor-1 potently inhibited cap-dependent translation in a dose-dependent manner in zebrafish embryos without causing developmental abnormalities and prevented eIF4E from triggering EMT in zebrafish ectoderm explants without toxicity. Metabolism studies with whole cell lysates demonstrated that the prodrug was rapidly converted into 7-BnGMP. Thus we have successfully developed the first nontoxic small molecule able to inhibit EMT, a key process in the development of epithelial cancer and tissue fibrosis, by targeting the interaction of eIF4E with the mRNA cap and demonstrated the tractability of zebrafish as a model organism for studying agents that modulate EMT. Our work provides strong motivation for the continued development of compounds designed to normalize cap-dependent translation as novel chemo-preventive agents and therapeutics for cancer and fibrosis.

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Available from: Alexey O Benyumov
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    • "Previously, Darzynkiewicz et al. [19] have shown that mRNA capped with Bn 7 GpppG was able to enhance translation efficacy 1.8-fold greater than Me 7 -capped transcripts. In addition, Ghosh et al. have demonstrated that Bn 7 -GMP binds tightly to eIF4E (K d ¼ 0.8 mM) and that a corresponding tryptamine phosphoramidate pronucleotide is a potent inhibitor of not only reticulocyte translation, but also the epithelial-to-mesenchymal transition (EMT) in zebra fish [20]. A recent crystallographic study with cocrystals of Bn 7 -GMP and eIF4E revealed that one of the tryptophan side chains involved in a critical p-cation stacking interaction Me 7 guanosine of capped mRNA had adopted a 180 ring flip conformation when bound to Bn 7 -GMP, allowing access by the benzyl moiety to a more pronounced hydrophobic pocket (Fig. 1). "
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    ABSTRACT: Aberrant regulation of cap-dependent translation has been frequently observed in the development of cancer. Association of the cap-binding protein eIF4E with N(7)-methylated guanosine capped mRNA is the rate limiting step governing translation initiation; and therefore represents an attractive process for cancer drug discovery. Previously, replacement of the 7-Me group of the Me(7)-guanosine monophosphate with a benzyl group has been found to increase binding affinity to eIF4E. Recent X-ray crystallographic studies have revealed that the cap-binding pocket undergoes a unique structural change in order to accommodate the benzyl group. To explore the structure-activity relationships governing the affinity of N(7)-benzylated guanosine monophosphate (Bn(7)-GMP) for eIF4E, we virtually screened a library of 80 Bn(7)-GMP analogs utilizing CombiGlide as implemented in Schrodinger. A subset library of substituted Bn(7)-GMP analogs was synthesized and their dissociation constants (K(d)) were determined. Due to the poor correlation between docking/scoring results and experimental binding affinities, three-dimensional quantitative structure-activity relationship (3D-QSAR) calculations were performed. Two highly predictive and self-consistent CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) models were derived and optimized. These models may be useful for the future design of eIF4E cap-binding antagonists.
    Full-text · Article · Apr 2010 · European Journal of Medicinal Chemistry
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