ArticleeLife2024
Ribosome subunit attrition and activation of the p53-MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition.
Article in eLife, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 18 citations in OpenAlex.
- Decoding WDR5-Mediated Interactions in Gliomas: Implications for Targeted Therapy.Medicinal research reviews · 2026Review
- Development and characterization of triazole-based WDR5 inhibitors for the treatment of glioblastoma.JCI insight · 2026Article
- Mammary Fibroblasts Secrete Damage Associated Molecular Patterns Through Extracellular Vesicles in Response to Ionizing Radiation.Journal of extracellular biology · 2026Article
- Epithelial hypusination regulates Helicobacter pylori-induced gastric inflammation.Amino acids · 2026Article
- Article
- The Incoming Influenza Genome Assembles a Host RBP Network that Orchestrates Viral RNA Synthesis.bioRxiv : the preprint server for biology · 2025Article
- Epithelial Hypusination Regulates Helicobacter pylori-induced Gastric Inflammation.Research square · 2025Article
- Chromatin Regulatory Targets for Anticancer Therapeutics.Chemical reviews · 2025Review
- Exosomes are specialized vehicles to induce fibronectin assembly.bioRxiv : the preprint server for biology · 2025Article
- Kaiso mediates transcription and RNA splicing in colorectal carcinoma: role of BRCA1 in the Kaiso enhanceosome.Open biology · 2025Article
- Article
- Pharmacologic degradation of WDR5 suppresses oncogenic activities of SS18::SSX and provides a therapeutic of synovial sarcoma.Science advances · 2025Article
- Ribosome-directed cancer therapies: the tip of the iceberg?Trends in pharmacological sciences · 2025Review
- SURF2 is a MDM2 antagonist in triggering the nucleolar stress response.Nature communications · 2024Article
- Expanded profiling of WD repeat domain 5 inhibitors reveals actionable strategies for the treatment of hematologic malignancies.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- WD Repeat Domain 5 Inhibitors for Cancer Therapy: Not What You Think.Journal of clinical medicine · 2024Review
- Article
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Authors and funding
20 authors at 2 institutions in 1 country.
Funding
Abstract
The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the 'WIN' site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small-molecule WINi, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anticancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in human MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anticancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies.
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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.