ArticleNucleic acids research2020
Discovery and development of novel DNA-PK inhibitors by targeting the unique Ku-DNA interaction.
Article in Nucleic acids research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 44 citations in OpenAlex.
- Design, synthesis, and structure-activity relationship studies of 4-substituted phenylpyrazolidinone derivatives as potent Ku70/80 targeted DNA-PK inhibitors.RSC medicinal chemistry · 2025Article
- Targeting DNA damage sensors for cancer therapy.DNA repair · 2025Review
- Impact of Optimized Ku-DNA Binding Inhibitors on the Cellular and In Vivo DNA Damage Response.Cancers · 2024Article
- Identification and Validation of New DNA-PKcs Inhibitors through High-Throughput Virtual Screening and Experimental Verification.International journal of molecular sciences · 2024Article
- Improving homology-directed repair by small molecule agents for genetic engineering in unconventional yeast?-Learning from the engineering of mammalian systems.Microbial biotechnology · 2024Review
- BRD7 enhances the radiosensitivity of nasopharyngeal carcinoma cells by negatively regulating USP5/METTL3 axis-mediated homologous recombination repair.International journal of biological sciences · 2024Article
- Ku-DNA binding inhibitors modulate the DNA damage response in response to DNA double-strand breaks.NAR cancer · 2023Article
- The N-Myc-responsive lncRNA MILIP promotes DNA double-strand break repair through non-homologous end joining.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Synthesis and Biological Evaluation of Cardiac Glycosides for Cancer Therapy by Targeting the DNA Damage Response.ChemMedChem · 2022Article
- Target residence of Cas9-sgRNA influences DNA double-strand break repair pathway choices in CRISPR/Cas9 genome editing.Genome biology · 2022Article
- Improved and Flexible HDR Editing by Targeting Introns in iPSCs.Stem cell reviews and reports · 2022Article
- Article
- Physical ARTEMIS:DNA-PKcs interaction is necessary for V(D)J recombination.Nucleic acids research · 2022Article
- Article
- Recent Advances in the Development of Non-PIKKs Targeting Small Molecule Inhibitors of DNA Double-Strand Break Repair.Frontiers in oncology · 2022Review
- Advance trends in targeting homology-directed repair for accurate gene editing: An inclusive review of small molecules and modified CRISPR-Cas9 systems.BioImpacts : BI · 2022Review
- Nucleic Acid Sensing Pathways in DNA Repair Targeted Cancer Therapy.Frontiers in cell and developmental biology · 2022Review
- The Multifaceted Roles of Ku70/80.International journal of molecular sciences · 2021Review
- Dynamics and competition of CRISPR-Cas9 ribonucleoproteins and AAV donor-mediated NHEJ, MMEJ and HDR editing.Nucleic acids research · 2021Article
- DNA Double Strand Break Repair Pathways in Response to Different Types of Ionizing Radiation.Frontiers in genetics · 2021Review
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 1 country.
Funding
Abstract
DNA-dependent protein kinase (DNA-PK) plays a critical role in the non-homologous end joining (NHEJ) repair pathway and the DNA damage response (DDR). DNA-PK has therefore been pursued for the development of anti-cancer therapeutics in combination with ionizing radiation (IR). We report the discovery of a new class of DNA-PK inhibitors that act via a novel mechanism of action, inhibition of the Ku-DNA interaction. We have developed a series of highly potent and specific Ku-DNA binding inhibitors (Ku-DBi's) that block the Ku-DNA interaction and inhibit DNA-PK kinase activity. Ku-DBi's directly interact with the Ku and inhibit in vitro NHEJ, cellular NHEJ, and potentiate the cellular activity of radiomimetic agents and IR. Analysis of Ku-null cells demonstrates that Ku-DBi's cellular activity is a direct result of Ku inhibition, as Ku-null cells are insensitive to Ku-DBi's. The utility of Ku-DBi's was also revealed in a CRISPR gene-editing model where we demonstrate that the efficiency of gene insertion events was increased in cells pre-treated with Ku-DBi's, consistent with inhibition of NHEJ and activation of homologous recombination to facilitate gene insertion. These data demonstrate the discovery and application of new series of compounds that modulate DNA repair pathways via a unique mechanism of action.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.