ArticleNature communications2021
The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma.
Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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Who cites it
63 citing papers in PubMed, 88 citations in OpenAlex.
- A selective NVL inhibitor suppresses tumor growth by targeting ribosome biogenesis.Nature chemical biology · 2026Article
- JP-1302 inhibits RNA polymerase I transcription and induces nucleolar stress in cancer cell lines.Cell death discovery · 2026Article
- G-quadruplex structures as regulators of cellular processes and drivers of genome instability in cancer.Critical reviews in biochemistry and molecular biology · 2026Review
- Active RNA synthesis patterns nuclear condensates.Cell systems · 2026Article
- Alternative Splicing of the NF-Y Subunit, NF-YA, in Neuroblastoma Phenotype Heterogeneity.Cancers · 2026Review
- CX-5461 and doxorubicin activate a shared DNA damage-associated transcriptional response in human cardiomyocytes.G3 (Bethesda, Md.) · 2026Article
- Ribosome biogenesis as a potential therapeutic target in KRAS mutant colorectal cancer.Nature communications · 2025Article
- An open-source screening platform accelerates discovery of drug combinations.Nature communications · 2025Article
- How DNA secondary structures drive replication fork instability.DNA repair · 2025Review
- Targeting RNA polymerase I to boost natural killer cell anticancer activity in multiple myeloma.Cell death & disease · 2025Article
- Dual RNA Polymerase I Inhibition with CX-5461 and BMH-21 Synergizes in Breast Cancer by Activating p53-Dependent Stress.bioRxiv : the preprint server for biology · 2025Article
- Prodrug florfenicol amine is activated by intrinsic resistance to target Mycobacterium abscessus.Nature microbiology · 2025Article
- NSH76: a selective inhibitor of RRN3 and RNA polymerase I transcription with potential for cancer therapy.Journal of translational medicine · 2025Article
- ATRX cooperates with TOP2B for replication fork stability and DNA damage response through G-quadruplex regulation.Nucleic acids research · 2025Article
- Molecular recognition and effects of a benzothiazole derivative targeting the MYC G-quadruplex.Nucleic acids research · 2025Article
- Anticancer drug development against ribosome synthesis and the nucleolus.Biochemical Society transactions · 2025Article
- Combining network pharmacology and RNA sequencing to reveal the mechanism of emodin for the treatment of human neuroblastoma.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- Review
- Ribosomal RNA transcription regulates splicing through ribosomal protein RPL22.Cell chemical biology · 2025Article
- Consistently processed RNA sequencing data from 50 sources enriched for pediatric data.Scientific data · 2025Article
3 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
30 authors at 3 institutions in 1 country.
Funding
Abstract
Survival in high-risk pediatric neuroblastoma has remained around 50% for the last 20 years, with immunotherapies and targeted therapies having had minimal impact. Here, we identify the small molecule CX-5461 as selectively cytotoxic to high-risk neuroblastoma and synergistic with low picomolar concentrations of topoisomerase I inhibitors in improving survival in vivo in orthotopic patient-derived xenograft neuroblastoma mouse models. CX-5461 recently progressed through phase I clinical trial as a first-in-human inhibitor of RNA-POL I. However, we also use a comprehensive panel of in vitro and in vivo assays to demonstrate that CX-5461 has been mischaracterized and that its primary target at pharmacologically relevant concentrations, is in fact topoisomerase II beta (TOP2B), not RNA-POL I. This is important because existing clinically approved chemotherapeutics have well-documented off-target interactions with TOP2B, which have previously been shown to cause both therapy-induced leukemia and cardiotoxicity-often-fatal adverse events, which can emerge several years after treatment. Thus, while we show that combination therapies involving CX-5461 have promising anti-tumor activity in vivo in neuroblastoma, our identification of TOP2B as the primary target of CX-5461 indicates unexpected safety concerns that should be examined in ongoing phase II clinical trials in adult patients before pursuing clinical studies in children.
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