ArticleBiochemistry2023
Identification of 2-Sulfonyl/Sulfonamide Pyrimidines as Covalent Inhibitors of WRN Using a Multiplexed High-Throughput Screening Assay.
Article in Biochemistry, 2023. 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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Who cites it
13 citing papers in PubMed, 28 citations in OpenAlex.
- 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
- Multidrug Resistance: Are We Still Afraid of the Big Bad Wolf.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Discovery of ATX968: An Orally Available Allosteric Inhibitor of DHX9.Journal of medicinal chemistry · 2025Article
- Werner helicase as a therapeutic target in mismatch repair deficient colorectal cancer.DNA repair · 2025Review
- 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
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Authors and funding
19 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Werner syndrome protein (WRN) is a multifunctional enzyme with helicase, ATPase, and exonuclease activities that are necessary for numerous DNA-related transactions in the human cell. Recent studies identified WRN as a synthetic lethal target in cancers characterized by genomic microsatellite instability resulting from defects in DNA mismatch repair pathways. WRN's helicase activity is essential for the viability of these high microsatellite instability (MSI-H) cancers and thus presents a therapeutic opportunity. To this end, we developed a multiplexed high-throughput screening assay that monitors exonuclease, ATPase, and helicase activities of full-length WRN. This screening campaign led to the discovery of 2-sulfonyl/sulfonamide pyrimidine derivatives as novel covalent inhibitors of WRN helicase activity. The compounds are specific for WRN versus other human RecQ family members and show competitive behavior with ATP. Examination of these novel chemical probes established the sulfonamide NH group as a key driver of compound potency. One of the leading compounds, H3B-960, showed consistent activities in a range of assays (IC
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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.