biostudies-literatureVolegova MPNCATS NIH HHSAlex's Lemonade Stand Foundation for Childhood CancerNCI NIH HHSNational Institutes of HealthNIGMS NIH HHS114134https://www.ebi.ac.uk/biostudies/studies/S-EPMC11284644biostudies-literatureUnknown43(5)Tumor MYCN amplification is seen in high-risk neuroblastoma, yet direct targeting of this oncogenic transcription factor has been challenging. Here, we take advantage of the dependence of MYCN-amplified neuroblastoma cells on increased protein synthesis to inhibit the activity of eukaryotic translation initiation factor 4A1 (eIF4A1) using an amidino-rocaglate, CMLD012824. Consistent with the role of this RNA helicase in resolving structural barriers in 5' untranslated regions (UTRs), CMLD012824 increased eIF4A1 affinity for polypurine-rich 5' UTRs, including that of the MYCN and associated transcripts with critical roles in cell proliferation. CMLD012824-mediated clamping of eIF4A1 spanned the full lengths of mRNAs, while translational inhibition was mediated through 5' UTR binding in a caCell reportsThe MYCN 5' UTR as a therapeutic target in neuroblastoma.PMC11284644R35 GM118173R21 CA267521U01 TR002625Banerjee UGeorge RESharma BKennedy AVolegova MPPorco JADries RBrown LEfalseThe MYCN 5' UTR as a therapeutic target in neuroblastoma.Tumor MYCN amplification is seen in high-risk neuroblastoma, yet direct targeting of this oncogenic transcription factor has been challenging. Here, we take advantage of the dependence of MYCN-amplified neuroblastoma cells on increased protein synthesis to inhibit the activity of eukaryotic translation initiation factor 4A1 (eIF4A1) using an amidino-rocaglate, CMLD012824. Consistent with the role of this RNA helicase in resolving structural barriers in 5' untranslated regions (UTRs), CMLD012824 increased eIF4A1 affinity for polypurine-rich 5' UTRs, including that of the MYCN and associated transcripts with critical roles in cell proliferation. CMLD012824-mediated clamping of eIF4A1 spanned the full lengths of mRNAs, while translational inhibition was mediated through 5' UTR binding in a ca2024-01-01T00:00:00Z2024 May2026-06-02T23:35:09.754Z2025-04-19T13:12:24.609ZS-EPMC112846443866254210.1016/j.celrep.2024.114134