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The MYC mRNA 3'-untranslated region (3'-UTR) is a pivotal regulatory domain within the transcript of the MYC proto-oncogene, which encodes a transcription factor essential for cell growth and proliferation (PMID: 31439716). This region serves as a hub for post-transcriptional control, containing binding sites for various microRNAs (e.g., let-7, miR-34a) and RNA-binding proteins that dictate the half-life and translation rate of the mRNA (PMID: 28630057). In many malignancies, mutations or deletions within the 3'-UTR, or the loss of its regulatory partners, lead to the stabilization of MYC mRNA and subsequent protein overexpression, driving oncogenesis (Nature Reviews Cancer, 2012). Given that the MYC protein lacks a traditional small-molecule binding pocket, the 3'-UTR has emerged as an attractive alternative therapeutic target. Current drug development strategies include the use of antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) to trigger RNase H-mediated or RISC-mediated degradation of the transcript (PMID: 33154511). Additionally, small molecules are being explored to stabilize specific RNA secondary structures, such as G-quadruplexes, within the 3'-UTR to block translation (PMID: 29156811). While promising, targeting this region faces challenges such as ensuring tumor-specific delivery and avoiding toxicity in normal tissues where MYC function is required for homeostasis.
Inhibition of MYC protein synthesis through sequence-specific mRNA degradation (via RNase H or RISC complex) or translational blockade by targeting regulatory elements and secondary structures within the 3'-UTR.
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