Aberrant translational control is emerging as a key feature of tumorigenesis and tumor progression across cancer types. The mTORC1/4EBP1/eIF4E axis, in particular, is a major regulator of translation initiation and driver of oncogenesis. The oncogene eIF4E binds to the 5’-m7GpppX cap of mRNA to initiate translation by recruiting the eIF4F complex, which comprises the scaffolding molecule eIF4G and the RNA helicase eIF4A. 4EBP1 is an antagonist of mRNA translation and prevents eIF4F complex formation. 4EBP1 is phosphorylated and inhibited by the mechanistic target of rapamycin (mTOR) kinase complex 1 (mTORC1). These downstream translational effectors play critical roles in the progression of many human cancers by promoting the expression of cancer-promoting proteins such as oncogenes and growth and survival factors. Although mTORC1-targeted kinase inhibitors have been widely explored in the clinic, these agents have largely been unsuccessful and many drug resistance mechanisms have been identified. Direct targeting of eIF4E has also been explored as an alternative approach for inhibiting this pathway, predominantly by antagonizing the eIF4E/m7GpppX interaction. Small molecule eIF4E inhibitors have largely been derived from m7GMP, and due to the presence of a phosphate, have suffered from poor cellular permeability and poor in vivo activity. To overcome these challenges, in this talk, I will describe our efforts toward the design, synthesis and biological evaluation of a new class of cell-permeable small molecule inhibitors of the eIF4E/m7GpppX interaction.

Cell permeable m7GMP-derived inhibitors for targeting the eIF4E/m7GpppX Interaction: An approach to combat aberrant cap-dependent translation in cancer

ACS Fall 2021

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