Second-Generation Cap Analogue Prodrugs for Targeting Aberrant Eukaryotic Translation Initiation Factor 4E (eIF4E)...

Melanoma is the deadliest form of skin cancer with a 5-year survival rate of less than 20%. While significant strides have been made in the field of kinase-targeted and immune-based therapies for melanoma, the development of resistance to these therapeutic agents has hindered the success of treatment. Drug-resistant melanoma is particularly reliant on enhanced cap-dependent translation to drive the production of oncoproteins that promote growth and survival. The m⁷GpppX cap-binding protein eukaryotic translation initiation factor 4E (eIF4E) is the rate-limiting factor of cap-dependent translation initiation, and its overexpression in melanoma tumors has been shown to drive resistance to BRAF^V600E kinase-targeted inhibitors. These findings point to eIF4E-targeted therapies as a promising strategy to overcome drug resistance in melanoma. Herein, we build upon our previous work of developing cell-permeable cap analogue inhibitors to design second-generation cap analogues that inhibit eIF4E-mediated cap-dependent translation in drug-resistant melanoma cells.