ArticleAssay and drug development technologies2012
A high-throughput scintillation proximity-based assay for human DNA ligase IV.
Article in Assay and drug development technologies, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
13 citing papers in PubMed, 15 citations in OpenAlex.
- An unexpected role of CLASP1 in radiation response and S-phase regulation of head and neck cancer cells.PloS one · 2025Article
- Mammalian DNA ligases; roles in maintaining genome integrity.Journal of molecular biology · 2024Review
- Review
- The Mutational Landscape of Cancer's Vulnerability to Ionizing Radiation.Clinical cancer research : an official journal of the American Association for Cancer Research · 2022Article
- DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer.Signal transduction and targeted therapy · 2020Review
- A unique DNA-binding mode of African swine fever virus AP endonuclease.Cell discovery · 2020Article
- Structure of the error-prone DNA ligase of African swine fever virus identifies critical active site residues.Nature communications · 2019Article
- Article
- Integrative radiogenomic profiling of squamous cell lung cancer.Cancer research · 2013Article
- A novel high throughput 1536-well Notch1 γ -secretase AlphaLISA assay.Combinatorial chemistry & high throughput screening · 2013Article
- DNA ligases as therapeutic targets.Translational cancer research · 2013Article
- A high-content biosensor-based screen identifies cell-permeable activators and inhibitors of EGFR function: implications in drug discovery.Journal of biomolecular screening · 2012Article
- A high throughput scintillation proximity imaging assay for protein methyltransferases.Combinatorial chemistry & high throughput screening · 2012Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Ionizing radiation (IR) and certain chemotherapeutic drugs are designed to generate cytotoxic DNA double-strand breaks (DSBs) in cancer cells. Inhibition of the major DSB repair pathway, nonhomologous end joining (NHEJ), will enhance the cytotoxicity of these agents. Screening for inhibitors of the DNA ligase IV (Lig4), which mediates the final ligation step in NHEJ, offers a novel target-based drug discovery opportunity. For this purpose, we have developed an enzymatic assay to identify chemicals that block the transfer of [α-(33)P]-AMP from the complex Lig4-[α-(33)P]-AMP onto the 5' end of a double-stranded DNA substrate and adapted it to a scintillation proximity assay (SPA). A screen was performed against a collection of 5,280 compounds. Assay statistics show an average Z' value of 0.73, indicative of a robust assay in this SPA format. Using a threshold of >20% inhibition, 10 compounds were initially scored as positive hits. A follow-up screen confirmed four compounds with IC(50) values ranging from 1 to 30 μM. Rabeprazole and U73122 were found to specifically block the adenylate transfer step and DNA rejoining; in whole live cell assays, these compounds were found to inhibit the repair of DSBs generated by IR. The ability to screen and identify Lig4 inhibitors suggests that they may have utility as chemo- and radio-sensitizers in combination therapy and provides a rationale for using this screening strategy to identify additional inhibitors.
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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.