ArticleCancer research2025
A Potent, Selective, Small-Molecule Inhibitor of DHX9 Abrogates Proliferation of Microsatellite Instable Cancers with Deficient Mismatch Repair.
Article in Cancer research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Synthetic lethality in cancer: mechanisms, therapeutic exploitation and clinical translation.Signal transduction and targeted therapy · 2026Review
- DDX21 Enhances Radiosensitivity in Head and Neck Squamous Cell Carcinoma by Suppressing MK2-Mediated DNA Damage Response.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- DHX9 Inhibition Enhances Paclitaxel Sensitivity by Inducing Mitotic Failure in Ovarian and Endometrial Cancers.Molecular cancer therapeutics · 2026Article
- R-loops in colorectal cancer: mechanisms, mapping strategies, and therapeutic opportunities.Molecular biology reports · 2026Review
- Fragment-Based Discovery of Potent RNA-Competitive Inhibitors of the DEAH-Box RNA Helicase DHX8.Journal of medicinal chemistry · 2026Article
- KDM4B/DHX9 promotes chemoresistance in small-cell lung cancer through the MYCN-driven signaling pathway.Oncogene · 2026Article
- Multi-omics dissection of R-loop dynamics in tumorigenesis: From transcription-replication conflict to therapeutic targets.Molecular therapy. Oncology · 2026Review
- DHX9 sustains hematopoietic stem cell function in cooperation with H3 acetylation.Stem cell reports · 2026Article
- Regulation of RNA-binding proteins by small biomolecules.Nature reviews. Molecular cell biology · 2026Review
- KIF20A inhibits TRIM21-dependent ubiquitination of DHX9 to boost SOX2 stability, enhancing OSCC stemness and ferroptosis resistance.Cell death & disease · 2026Article
- Regulation of R-Loop Dynamics by Proteins and Long Noncoding RNAs: An Emerging Paradigm for Cancer Treatment.Cancer science · 2026Review
- 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
- Reduced R-loop abundance at proinflammatory loci: a shared epigenetic mechanism in inflammatory and metabolic diseases.Frontiers in cardiovascular medicine · 2026Article
- Inducing tumor-intrinsic innate immune response to break cancer immunotherapy resistance.Frontiers in medicine · 2026Review
- Orchestrating innate immunity through RNA editing and helicase activity: ADAR1, dsRNA sensors, and tumor immune evasion.Frontiers in cell and developmental biology · 2026Review
- Article
- DHX9-mediated epigenetic silencing of BECN1 contributes to impaired autophagy and tumor progression in breast cancer via recruitment of HDAC5.Cell death & disease · 2025Article
- Discovery of ATX968: An Orally Available Allosteric Inhibitor of DHX9.Journal of medicinal chemistry · 2025Article
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Authors and funding
24 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
DHX9 is a multifunctional DExH-box RNA helicase with important roles in the regulation of transcription, translation, and maintenance of genome stability. Elevated expression of DHX9 is evident in multiple cancer types, including colorectal cancer. Microsatellite instable-high (MSI-H) tumors with deficient mismatch repair (dMMR) display a strong dependence on DHX9, making this helicase an attractive target for oncology drug discovery. In this report, we show that DHX9 knockdown increased RNA/DNA secondary structures and replication stress, resulting in cell-cycle arrest and the onset of apoptosis in cancer cells with MSI-H/dMMR. ATX968 was identified as a potent and selective inhibitor of DHX9 helicase activity. Chemical inhibition of DHX9 enzymatic activity elicited similar selective effects on cell proliferation as seen with genetic knockdown. In addition, ATX968 induced robust and durable responses in an MSI-H/dMMR xenograft model but not in a microsatellite stable/proficient MMR model. These preclinical data validate DHX9 as a target for the treatment of patients with MSI-H/dMMR. Additionally, this potent and selective inhibitor of DHX9 provides a valuable tool with which to further explore the effects of inhibition of DHX9 enzymatic activity on the proliferation of cancer cells in vitro and in vivo. Significance: DHX9 is required in cancer cells with deficient mismatch repair and can be inhibited by ATX968, providing a promising strategy for the development of precision cancer therapeutics.
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