Nontoxic chemical interdiction of the epithelial-to-mesenchymal transition by targeting cap-dependent translation.
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.
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
Brahma
B
Ghosh
Alexey O
AO
Benyumov
Phalguni
P
Ghosh
Yan
Y
Jia
Svetlana
S
Avdulov
Peter S
PS
Dahlberg
Mark
M
Peterson
Karen
K
Smith
Vitaly A
VA
Polunovsky
Peter B
PB
Bitterman
Carston R
CR
Wagner
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D016503:Drug Delivery Systems; D004625:Embryo, Nonmammalian / Q000196:embryology; D004848:Epithelium / Q000196:embryology*; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D008648:Mesoderm / Q000196:embryology*; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000378:metabolism; D039502:Nuclear Cap-Binding Protein Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010756:Phosphoric Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015027:Zebrafish / Q000196:embryology*
D000577:Amides; D039561:Eukaryotic Initiation Factor-4E; D039502:Nuclear Cap-Binding Protein Complex; D010756:Phosphoric Acids; C011067:phosphoramidic acid