ArticleCancer discovery2024
Novel WRN Helicase Inhibitors Selectively Target Microsatellite-Unstable Cancer Cells.
Article in Cancer discovery, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
29 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Novel Therapeutic Strategies for Metastatic Prostate Cancer Care.European urology · 2025Pooled it
- CRISPR Screening Identifies SMARCAL1 and MRN as Modulators of WRN Dependency in MSI-H Colorectal Cancer.Cancer research · 2026Article
- Targeting WRN Helicase in Microsatellite-Instable Colorectal Cancer Induces Antitumor Immunity through Extrachromosomal Circular DNA Release.Cancer research · 2026Article
- A synthetic lethal drug for microsatellite instability cancers.Nature medicine · 2026Article
- Werner helicase inhibitor for advanced microsatellite instability solid tumors: a phase 1 trial.Nature medicine · 2026Article
- Article
- High-Content CRISPR Screening: Methods and Applications.MedComm · 2026Review
- Suppression of transcription-replication conflicts by sequence-coordinated actions of TRDMT1 and MutLα.Nature communications · 2026Article
- Microsatellite Instable Cancer Cells Acquire On-target Resistance Mutations to WRN Helicase Inhibitors.Molecular cancer therapeutics · 2026Article
- BEstimate: a computational tool for the design and interpretation of CRISPR base editing experiments.Genome biology · 2026Article
- Multiplexed TrAEL-seq captures DNA replication dynamics in mammalian cells.Nucleic acids research · 2026Article
- Design and synthesis of 2-amino-4-(trifluoromethyl)pyrimidine derivatives as potential Werner-dependent antiproliferative agents.Molecular diversity · 2026Article
- Structural insights into WRN helicase reveal conformational states and opportunities for MSI-H cancer drug discovery.Communications biology · 2026Article
- Targeting R-loops: diverse RNA helicases in R-loop resolution and their potential as targets for cancer therapy.Frontiers in cell and developmental biology · 2026Review
- Synthetic lethality in cancer drug discovery: challenges and opportunities.Nature reviews. Drug discovery · 2026Review
- A practical method for determining the rate of covalent modification of fragments and leads.Nature communications · 2025Article
- Review
- Review
- Mismatch Repair as a Dynamic and Clinically Actionable Vulnerability in Cancer.Cancer research · 2025Review
- Therapeutic targeting of mismatch repair-deficient cancers.Nature reviews. Clinical oncology · 2025Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
50 authors.
Funding
Abstract
Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumors, and WRN inhibitors are in development. In this study, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target. Fragment-based screening led to the development of potent and highly selective WRN helicase covalent inhibitors. These compounds selectively suppressed MSI model growth in vitro and in vivo by mimicking WRN loss, inducing DNA double-strand breaks at expanded TA repeats and DNA damage. Assessment of biomarkers in preclinical models linked TA-repeat expansions and mismatch repair alterations to compound activity. Efficacy was confirmed in immunotherapy-resistant organoids and patient-derived xenograft models. The discovery of potent, selective covalent WRN inhibitors provides proof of concept for synthetic lethal targeting of WRN in MSI cancer and tools to dissect WRN biology. Significance: We report the discovery and characterization of potent, selective WRN helicase inhibitors for MSI cancer treatment, with biomarker analysis and evaluation of efficacy in vivo and in immunotherapy-refractory preclinical models. These findings pave the way to translate WRN inhibition into MSI cancer therapies and provide tools to investigate WRN biology. See related commentary by Wainberg, p. 1369.
Indexed as
Identifiers
What OpenQuestion holds
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.