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bioRxiv · 10.1101/2024.09.25.614990

Second-Generation Cap Analogue Prodrugs for Targeting Aberrant Eukaryotic Translation Initiation Factor 4E (eIF4E) Activity in Drug-Resistant Melanoma

Cardenas, E. L.·O'Rourke, R. L.·Menon, A.·Vega Hernandez, G.·Meagher, J.·Stuckey, J.·Garner, A. L.
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Abstract

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 BRAFV600E 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.

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Cardenas, E. L., O'Rourke, R. L., Menon, A., Vega Hernandez, G., Meagher, J., Stuckey, J., Garner, A. L.. 2024-09-27. Second-Generation Cap Analogue Prodrugs for Targeting Aberrant Eukaryotic Translation Initiation Factor 4E (eIF4E) Activity in Drug-Resistant Melanoma. https://doi.org/10.1101/2024.09.25.614990

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