ArticleScience translational medicine2021
A selective WDR5 degrader inhibits acute myeloid leukemia in patient-derived mouse models.
Article in Science translational medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers.
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
81 citing papers in PubMed.
- An EZH2-SREBP2 axis promotes cholesterol biosynthesis and represents a noncanonical vulnerability in tumorigenesis.Nature cell biology · 2026Article
- The DNMT1 CXXC domain senses CpG islands for DNA methylation inhibition.Nature communications · 2026Article
- The role of the WD40-repeat protein family in cancer.Molecular cancer · 2026Review
- Targeting the MYCN interaction network in neuroblastoma.Bioscience reports · 2026Review
- Review
- Prospects and advances of PROTAC in the treatment of hematologic malignancies.Experimental hematology & oncology · 2026Review
- Mono-ubiquitination of histone H2A lysine 119 (H2AK119Ub): its multifaceted role in biology and implication in diseases.MedScience · 2026Review
- WDR5 remodels NANOG condensates to drive transcriptional programs and sustain stem cell identity.Nature communications · 2026Article
- In Silico Analysis of Potential Stabilizer Binding Sites at Protein-RNA Interfaces.Computational and structural biotechnology journal · 2026Article
- From Mechanism to Medicine: Peptide-Based Approaches for Cancer Diagnosis and Therapy.Biomolecules · 2025Review
- FUBP3 mediates MXI1 stability to silence RRAS and hinder MAPK signaling in acute megakaryoblastic leukemia progression.Cancer immunology, immunotherapy : CII · 2025Article
- Chemically-induced degradation of the endoplasmic-reticulum stress sensor IRE1 by a VHL-recruiting chimera.Nature communications · 2025Article
- Interpretable PROTAC Degradation Prediction With Structure-Informed Deep Ternary Attention Framework.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Advancing PROTAC Discovery Through Artificial Intelligence: Opportunities, Challenges, and Future Directions.Pharmaceuticals (Basel, Switzerland) · 2025Review
- PRosettaC outperforms AlphaFold3 for modeling PROTAC ternary complexes.Scientific reports · 2025Article
- Chromatin Regulatory Targets for Anticancer Therapeutics.Chemical reviews · 2025Review
- A Novel Multi-Tiered Hybrid Virtual Screening Pipeline for the Discovery of WDR5-MLL1 Interaction Disruptors in Precision Cancer Therapy.ACS omega · 2025Article
- Role of Histone H3 Lysine 4 Methylation in Chromatin Biology.Molecules (Basel, Switzerland) · 2025Review
- Review
- Data-Driven Generation of Conformational Ensembles and Ternary Complexes for PROTAC and Other Chimera Systems.Journal of chemical information and modeling · 2025Article
21 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
19 authors.
Funding
Abstract
Interactions between WD40 repeat domain protein 5 (WDR5) and its various partners such as mixed lineage leukemia (MLL) and c-MYC are essential for sustaining oncogenesis in human cancers. However, inhibitors that block protein-protein interactions (PPIs) between WDR5 and its binding partners exhibit modest cancer cell killing effects and lack in vivo efficacy. Here, we present pharmacological degradation of WDR5 as a promising therapeutic strategy for treating WDR5-dependent tumors and report two high-resolution crystal structures of WDR5-degrader-E3 ligase ternary complexes. We identified an effective WDR5 degrader via structure-based design and demonstrated its in vitro and in vivo antitumor activities. On the basis of the crystal structure of an initial WDR5 degrader in complex with WDR5 and the E3 ligase von Hippel–Lindau (VHL), we designed a WDR5 degrader, MS67, and demonstrated the high cooperativity of MS67 binding to WDR5 and VHL by another ternary complex structure and biophysical characterization. MS67 potently and selectively depleted WDR5 and was more effective than WDR5 PPI inhibitors in suppressing transcription of WDR5-regulated genes, decreasing the chromatin-bound fraction of MLL complex components and c-MYC, and inhibiting the proliferation of cancer cells. In addition, MS67 suppressed malignant growth of MLL-rearranged acute myeloid leukemia patient cells in vitro and in vivo and was well tolerated in vivo. Collectively, our results demonstrate that structure-based design can be an effective strategy to identify highly active degraders and suggest that pharmacological degradation of WDR5 might be a promising treatment for WDR5-dependent cancers.
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.