ArticleJournal of the American Chemical Society2020
Targeted Degradation of the Oncogenic MicroRNA 17-92 Cluster by Structure-Targeting Ligands.
Article in Journal of the American Chemical Society, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers, 1 of them a synthesis that pooled it.
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Who cites it
44 citing papers in PubMed, 1 synthesis or guideline pooled it, 79 citations in OpenAlex.
- Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins.Theranostics · 2021Pooled it
- DLRNA-BERTa: a transformer approach for predicting molecule-RNA binding affinities.Briefings in bioinformatics · 2026Article
- Article
- Predicting small molecule-RNA interactions without RNA tertiary structures.Nature biotechnology · 2026Article
- MicroRNA chemical modifications in post-transcriptional gene silencing and human diseases.Molecular therapy. Nucleic acids · 2025Review
- Targeted RNA Degradation as a Promising Therapeutic Strategy.International journal of molecular sciences · 2025Review
- [Targeting chimera technology: A new tool for undruggable in breast cancer].Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2025Review
- Xist condensates: perspectives for therapeutic intervention.Genome biology · 2025Review
- PROTAC and Molecular Glue Degraders of the Oncogenic RNA Binding Protein Lin28.Macromolecular bioscience · 2025Article
- A review on gut microbiota and miRNA crosstalk: implications for Alzheimer's disease.GeroScience · 2025Review
- Chemical-guided SHAPE sequencing (cgSHAPE-seq) informs the binding site of RNA-degrading chimeras targeting SARS-CoV-2 5' untranslated region.Nature communications · 2025Article
- The clinicopathological significance of BRI3BP in women with invasive breast cancer.Translational cancer research · 2024Article
- RNA Structure: Past, Future, and Gene Therapy Applications.International journal of molecular sciences · 2024Review
- Enhanced expression of miR-20a driven by nanog exacerbated the degradation of extracellular matrix in thoracic aortic dissection.Non-coding RNA research · 2024Article
- Impact of protein kinase CK2 downregulation and inhibition on oncomir clusters 17 ~ 92 and 106b ~ 25 in prostate, breast, and head and neck cancers.Molecular medicine (Cambridge, Mass.) · 2024Article
- Small-molecule-based targeted therapy in liver cancer.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Review
- Small molecules targeting microRNAs: new opportunities and challenges in precision cancer therapy.Trends in cancer · 2024Review
- Advancements in clinical RNA therapeutics: Present developments and prospective outlooks.Cell reports. Medicine · 2024Review
- Large-scale analysis of small molecule-RNA interactions using multiplexed RNA structure libraries.Communications chemistry · 2024Article
- Targeting MicroRNAs with Small Molecules.Non-coding RNA · 2024Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Many RNAs are processed into biologically active transcripts, the aberrant expression of which can contribute to disease phenotypes. For example, the primary microRNA-17-92 (pri-miR-17-92) cluster contains six microRNAs (miRNAs) that collectively act in several disease settings. Herein, we used sequence-based design of structure-specific ligands to target a common structure in the Dicer processing sites of three miRNAs in the cluster, miR-17, miR-18a, and miR-20a, thereby inhibiting their biogenesis. The compound was optimized to afford a dimeric molecule that binds the Dicer processing site and an adjacent bulge, affording a 100-fold increase in potency. The dimer's mode of action was then extended from simple binding to direct cleavage by conjugation to bleomycin A5 in a manner that imparts RNA-selective cleavage or to indirect cleavage by recruiting an endogenous nuclease, or a ribonuclease targeting chimera (RIBOTAC). Interestingly, the dimer-bleomycin conjugate cleaves the entire pri-miR-17-92 cluster and hence functionally inhibits all six miRNAs emanating from it. The compound selectively reduced levels of the cluster in three disease models: polycystic kidney disease, prostate cancer, and breast cancer, rescuing disease-associated phenotypes in the latter two. Further, the bleomycin conjugate exerted selective effects on the miRNome and proteome in prostate cancer cells. In contrast, the RIBOTAC only depleted levels of pre- and mature miR-17, -18a, and 20a, with no effect on the primary transcript, in accordance with the cocellular localization of RNase L, the pre-miRNA targets, and the compound. These studies demonstrate a strategy to tune RNA structure-targeting compounds to the cellular localization of the target.
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Registered trials
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