ArticleClinical cancer research : an official journal of the American Association for Cancer Research2011
The novel chemical entity YTR107 inhibits recruitment of nucleophosmin to sites of DNA damage, suppressing repair of DNA double-strand breaks and enhancing radiosensitization.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 28 citations in OpenAlex.
- Sensitising PDAC to Gemcitabine by Suppressing NF-κB Pathway and Enhancing Apoptosis.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Nucleophosmin 1 proteins as potential therapeutic targets in non-communicable chronic inflammatory diseases: a review of pathophysiological mechanisms.Frontiers in cell and developmental biology · 2026Review
- Review
- Nucleophosmin Plays a Role in Repairing DNA Damage and Is a Target for Cancer Treatment.Cancer research · 2023Review
- Metabolic Profiling ofMolecules (Basel, Switzerland) · 2022Article
- Targeting NPM1 in irradiated cells inhibits NPM1 binding to RAD51, RAD51 foci formation and radiosensitizes NSCLC.Cancer letters · 2021Article
- Epigenetic CRISPR Screens IdentifyCancer research · 2020Article
- Nucleophosmin in Its Interaction with Ligands.International journal of molecular sciences · 2020Review
- Phosphoproteome Profiling Reveals Multifunctional Protein NPM1 as part of the Irradiation Response of Tumor Cells.Translational oncology · 2019Article
- Molecules that target nucleophosmin for cancer treatment: an update.Oncotarget · 2016Review
- Protein expression of nucleophosmin, annexin A3 and nm23-H1 correlates with human nasopharyngeal carcinoma radioresistanceOncology letters · 2016Article
- 1-Benzyl-2-methyl-3-indolylmethylene barbituric acid derivatives: Anti-cancer agents that target nucleophosmin 1 (NPM1).Bioorganic & medicinal chemistry · 2015Article
- Development and validation of a novel assay to identify radiosensitizers that target nucleophosmin 1.Bioorganic & medicinal chemistry · 2015Article
- Nucleophosmin modulates stability, activity, and nucleolar accumulation of base excision repair proteins.Molecular biology of the cell · 2014Article
- Emerging roles of the nucleolus in regulating the DNA damage response: the noncanonical DNA repair enzyme APE1/Ref-1 as a paradigmatical example.Antioxidants & redox signaling · 2014Review
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
Abstract
purposeRadiation therapy continues to be an important therapeutic strategy for providing definitive local/regional control of human cancer. However, oncogenes that harbor driver mutations and/or amplifications can compromise therapeutic efficacy. Thus, there is a need for novel approaches that enhance the DNA damage produced by ionizing radiation. EXPERIMENTAL
designA forward chemical genetic approach coupled with cell-based phenotypic screening of several tumor cell lines was used to identify a novel chemical entity (NCE) that functioned as a radiation sensitizer. Proteomics, comet assays, confocal microscopy, and immunoblotting were used to identify the biological target.
resultsThe screening process identified a 5-((N-benzyl-1H-indol-3-yl)-methylene)pyrimidine-2,4,6(1H,3H,5H)trione as an NCE that radiosensitized cancer cells expressing amplified and/or mutated RAS, ErbB, PIK3CA, and/or BRAF oncogenes. Affinity-based solid-phase resin capture followed by liquid chromatography/tandem mass spectrometry identified the chaperone nucleophosmin (NPM) as the NCE target. SiRNA suppression of NPM abrogated radiosensitization by the NCE. Confocal microscopy showed that the NCE inhibited NPM shuttling to radiation-induced DNA damage repair foci, and the analysis of comet assays indicated a diminished rate of DNA double-strand break repair.
conclusionThese data support the hypothesis that inhibition of DNA repair due to inhibition of NPM shuttling increases the efficacy of DNA-damaging therapeutic strategies.
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Registered trials
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