Emilio L Cárdenas, Rachel L O'Rourke, Arya Menon, Gabriela Vega-Hernández, Jennifer Meagher, Jeanne Stuckey, Amanda L Garner
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Second-Generation Cap Analogue Prodrugs for Targeting Aberrant Eukaryotic Translation Initiation Factor 4E Activity in Cancer.
Dysregulation of translation is a hallmark of cancer that enables rapid changes in cellular protein production to shape oncogenic phenotypes. Translation initiation is governed by the m7GpppX cap-binding protein eukaryotic translation initiation factor 4E (eIF4E), the rate-limiting factor of cap-dependent translation initiation. eIF4E is overexpressed in many cancers and drives the production of oncoproteins that promote tumor growth and survival. Accordingly, eIF4E has been established as an attractive albeit challenging therapeutic target. Building upon our previous work of developing cell-permeable cap analogue prodrugs that inhibit eIF4E binding to the m7GpppX cap, herein we disclose the design of second-generation cap analogues with alternative N-9-substituted linkers which exhibit anticancer activity in BRAFV600E mutant melanoma cell lines.
期刊介绍：
ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to:
Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics)
Biological characterization of new molecular entities in the context of drug discovery
Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc.
Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry
Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources
Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response
Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic
Mechanistic drug metabolism and regulation of metabolic enzyme gene expression
Chemistry patents relevant to the medicinal chemistry field.
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