Design of Cell-Permeable Inhibitors of Eukaryotic Translation Initiation Factor 4E (eIF4E) for Inhibiting Aberrant Cap-Dependent Translation in Cancer

Sep 24, 2026

Eukaryotic translation initiation factor 4E (eIF4E) is an RNA-binding protein that recognizes the m7GpppX cap at the 5′ end of coding mRNAs to initiate cap-dependent translation. Although essential in all cells, cancer cells become dependent on enhanced translation capacity, supporting oncogenic programs such as proliferation, apoptosis evasion, metastasis, and angiogenesis. eIF4E acts as a rate-limiting factor whose activation drives tumor initiation, progression, resistance, and drug failure, making it a promising but challenging anticancer target. This work addresses cell-permeable, cap-competitive inhibition by synthesizing cell-permeable eIF4E binders using an acyclic nucleoside phosphonate prodrug strategy.

LanguageEnglish

CategoryHealthcare

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Reading Time1 h 48 min

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Abstract

Introduction

eIF4E and cap-dependent translation in cancer

bioRxiv preprint doi: [https://doi.org/10.1101/2023.05.23.541912](https://doi.org/10.1101/2023.05.23.541912); this version posted May 24, 2023. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Design of Cell-Permeable Inhibitors of Eukaryotic Translation Initiation Factor 4E (eIF4E) for Inhibiting Aberrant Cap-Dependent Translation in Cancer Emilio L. Cárdenas1, Rachel L. O’Rourke 1, Arya Menon 1, Jennifer Meagher2, Jeanne Stuckey2,3, and Amanda L. Garner 1* 1Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States 2Life Science Institute, University of Michigan, Ann Arbor, Michigan 48109, United States 3Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States *Email: [algarner@umich.edu](algarner@umich.edu) bioRxiv preprint doi: [https://doi.org/10.1101/2023.05.23.541912](https://doi.org/10.1101/2023.05.23.541912); this version posted May 24, 2023. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. ABSTRACT: Eukaryotic translation initiation factor 4E (eIF4E) is an RNA-binding protein that binds to them7GpppX-cap at the 5¢ terminus of coding mRNAs to initiate cap-dependent translation. While all cells require cap-dependent translation, cancer cells become addicted to enhanced translational capacity, driving the production of oncogenic proteins involved in proliferation, evasion of apoptosis, metastasis, and angiogenesis among other cancerous phenotypes. eIF4E is the ratelimiting translation factor and its activation has been shown to drive cancer initiation, progression, metastasis, and drug resistance. These findings have established eIF4E as a translational oncogene and promising, albeit challenging, anti-cancer therapeutic target. Although significant effort has been put forth towards inhibiting eIF4E, the design of cell-permeable, cap-competitive inhibitors remains a challenge. Herein, we describe our work towards solving this long-standing challenge. By employing an acyclic nucleoside phosphonate prodrug strategy, we report the synthesis of cellpermeable inhibitors of eIF4E binding to capped mRNA to inhibit cap-dependent translation. bioRxiv preprint doi: [https://doi.org/10.1101/2023.05.23.541912](https://doi.org/10.1101/2023.05.23.541912); this version posted May 24, 2023. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. INTRODUCTION: Protein synthesis is the penultimate step of gene expression, dynamically controlling the makeup of the proteome in response to cellular stimuli. While all cells require protein synthesis, cancer cells, in particular, become addicted to enhanced translational capacity, driving the production of proteins necessary for proliferation and survival, in addition to other hallmarks of cancer.1-3 Indeed, in cancer, changes in mRNA translation have been shown to be more extensive than changes in transcription, enabling the cell to use existing mRNA pools to quickly regulate cellular state and activity.3, 4 Although many mechanisms lead to dysregulation of translational control in cancer, the predominant paths are through hyperactivation of the PI3K-AKT-mTORC1 and RASRAF-MAPK, and MYC signaling pathways,5, 6 all of which converge on the regulation of capdependent mRNA translation, the major translational program leading to the translation of mRNAs encoding oncoproteins and growth and survival factors including c-Myc, cyc

FAQs

Why is eIF4E considered an important anticancer target?

eIF4E drives cap-dependent translation, and its activation is linked to cancer initiation, progression, metastasis, and drug resistance. Reducing eIF4E can impede cancer cell growth and survival programs.

What limitation makes current eIF4E inhibitor design difficult?

Although significant efforts have been made to inhibit eIF4E, designing cell-permeable, cap-competitive inhibitors remains challenging.

How does this study aim to create effective eIF4E inhibitors?

The approach uses an acyclic nucleoside phosphonate prodrug strategy to synthesize cell-permeable inhibitors that bind eIF4E and inhibit capped-mRNA-driven translation.

Sep 24, 2026

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