Second-Generation\nCap Analogue Prodrugs for Targeting\nAberrant Eukaryotic Translation Initiation Factor 4E Activity in Cancer

Dysregulation of translation is a\nhallmark of cancer\nthat enables\nrapid changes in cellular protein production to shape oncogenic phenotypes.\nTranslation initiation is governed by the m<sup>7</sup>GpppX cap-binding\nprotein eukaryotic translation initiation factor 4E (eIF4E), the rate-limiting\nfactor of cap-dependent translation initiation. eIF4E is overexpressed\nin many cancers and drives the production of oncoproteins that promote\ntumor growth and survival. Accordingly, eIF4E has been established\nas an attractive albeit challenging therapeutic target. Building upon\nour previous work of developing cell-permeable cap analogue prodrugs\nthat inhibit eIF4E binding to the m<sup>7</sup>GpppX cap, herein we\ndisclose the design of second-generation cap analogues with alternative <i>N</i>-9-substituted linkers which exhibit anticancer activity\nin BRAF<sup>V600E</sup> mutant melanoma cell lines.