4Ei-10 interdiction of oncogenic cap-mediated translation as therapy for non-small cell lung cancer

Blake A. Jacobson, Zeeshan Ahmad, Sierra Chen, Gabriella Waldusky, Maxwell Dillenburg, Emilia Stoian, Daniel A. Cambron, Anil J. Patel, Manish R Patel, Carston R Wagner, Robert A. Kratzke

Research output: Contribution to journalArticlepeer-review

Abstract

In order to suppress 5′ cap-mediated translation a highly available inhibitor of the interaction between the 5’ mRNA cap and the eIF4E complex has been developed. 4Ei-10 is a member of the class of ProTide compounds and has elevated membrane permeability and is a strong active chemical antagonist for eIF4E. Once taken up by cells it is converted by anchimeric activation of the lipophilic 2-(methylthio) ethyl protecting group and after that Hint1 P-N bond cleavage to N7-(p-chlorophenoxyethyl) guanosine 5′-monophosphate (7-Cl-Ph-Ethyl-GMP). Using this powerful interaction, it has been demonstrated that 4Ei-10 inhibits non-small cell lung cancer (NSCLC) cell growth. In addition, treatment of NSCLC cells with 4Ei-10 results in suppression of translation and diminished expression of a cohort of cellular proteins important to maintaining the malignant phenotype and resisting apoptosis such as Bcl-2, survivin, and ornithine decarboxylase (ODC). Finally, as a result of targeting the translation of anti-apoptotic proteins, NSCLC cells are synergized to be more sensitive to the existing anti-neoplastic treatment gemcitabine currently used in NSCLC therapy.

Original languageEnglish (US)
JournalInvestigational New Drugs
DOIs
StateAccepted/In press - 2020

Bibliographical note

Funding Information:
The work was supported by the John Skoglund Fund for Lung Cancer Research at the University of Minnesota.

Keywords

  • 4Ei-10
  • Cap-dependent translation
  • eIF4E
  • eIF4G
  • Non-small cell lung cancer
  • ProTide

PubMed: MeSH publication types

  • Journal Article

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