ArticlePloS one2019
A high-throughput screen to identify novel small molecule inhibitors of the Werner Syndrome Helicase-Nuclease (WRN).
Article in PloS one, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 46 citations in OpenAlex.
- Shuttling of RecQ helicase HIM-6 coordinates iterative cycle of unwinding, pulling, and backsliding.Nucleic acids research · 2026Article
- Structural insights into WRN helicase reveal conformational states and opportunities for MSI-H cancer drug discovery.Communications biology · 2026Article
- WRN structural flexibility showcased through fragment-based lead discovery of inhibitors.Nature communications · 2026Article
- Identification of VVD-214/RO7589831, a Clinical-Stage, Covalent Allosteric Inhibitor of WRN Helicase for the Treatment of MSI-High Cancers.Journal of medicinal chemistry · 2025Article
- Werner helicase as a therapeutic target in mismatch repair deficient colorectal cancer.DNA repair · 2025Review
- Specific Monitoring the DNA Helicase Function via Anchor-Embedded DNA Probe.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Design and synthesis of N-aryl-2-trifluoromethyl-quinazoline-4-amine derivatives as potential Werner-dependent antiproliferative agents.Molecular diversity · 2025Article
- Structure-based discovery of first inhibitors targeting the helicase activity of human PIF1.Nucleic acids research · 2024Article
- PROTAC-mediated conditional degradation of the WRN helicase as a potential strategy for selective killing of cancer cells with microsatellite instability.Scientific reports · 2024Article
- High throughput screening for SARS-CoV-2 helicase inhibitors.SLAS discovery : advancing life sciences R & D · 2024Article
- Novel WRN Helicase Inhibitors Selectively Target Microsatellite-Unstable Cancer Cells.Cancer discovery · 2024Article
- Article
- Identification of 2-Sulfonyl/Sulfonamide Pyrimidines as Covalent Inhibitors of WRN Using a Multiplexed High-Throughput Screening Assay.Biochemistry · 2023Article
- WRN rescues replication forks compromised by a BRCA2 deficiency: Predictions for how inhibition of a helicase that suppresses premature aging tilts the balance to fork demise and chromosomal instability in cancer.BioEssays : news and reviews in molecular, cellular and developmental biology · 2022Article
- DNA repair defects in cancer and therapeutic opportunities.Genes & development · 2022Review
- Review
- Recent Advances in the Development of Non-PIKKs Targeting Small Molecule Inhibitors of DNA Double-Strand Break Repair.Frontiers in oncology · 2022Review
- RecQ Helicase Somatic Alterations in Cancer.Frontiers in molecular biosciences · 2022Review
- Synthetic Lethal Interactions of RECQ Helicases.Trends in cancer · 2021Review
- Structure of the helicase core of Werner helicase, a key target in microsatellite instability cancers.Life science alliance · 2021Article
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
Werner syndrome (WS), an autosomal recessive genetic disorder, displays accelerated clinical symptoms of aging leading to a mean lifespan less than 50 years. The WS helicase-nuclease (WRN) is involved in many important pathways including DNA replication, recombination and repair. Replicating cells are dependent on helicase activity, leading to the pursuit of human helicases as potential therapeutic targets for cancer treatment. Small molecule inhibitors of DNA helicases can be used to induce synthetic lethality, which attempts to target helicase-dependent compensatory DNA repair pathways in tumor cells that are already genetically deficient in a specific pathway of DNA repair. Alternatively, helicase inhibitors may be useful as tools to study the specialized roles of helicases in replication and DNA repair. In this study, approximately 350,000 small molecules were screened based on their ability to inhibit duplex DNA unwinding by a catalytically active WRN helicase domain fragment in a high-throughput fluorometric assay to discover new non-covalent small molecule inhibitors of the WRN helicase. Select compounds were screened to exclude ones that inhibited DNA unwinding by other helicases in the screen, bound non-specifically to DNA, acted as irreversible inhibitors, or possessed unfavorable chemical properties. Several compounds were tested for their ability to impair proliferation of cultured tumor cells. We observed that two of the newly identified WRN helicase inhibitors inhibited proliferation of cancer cells in a lineage-dependent manner. These studies represent the first high-throughput screen for WRN helicase inhibitors and the results have implications for anti-cancer strategies targeting WRN in different cancer cells and genetic backgrounds.
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