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

Eukaryotic translation initiation factor 4E (eIF4E) is
an RNA-binding
protein that binds to the m7GpppX-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 rate-limiting
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 toward inhibiting eIF4E, the design of cell-permeable,
cap-competitive inhibitors remains a challenge. Herein, we describe
our work toward solving this long-standing challenge. By employing
an acyclic nucleoside phosphonate prodrug strategy, we report the
synthesis of cell-permeable inhibitors of eIF4E binding to capped
mRNA to inhibit cap-dependent translation.