ArticleJournal of medicinal chemistry2020
Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core.
Article in Journal of medicinal chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 30 citations in OpenAlex.
- Development and characterization of triazole-based WDR5 inhibitors for the treatment of glioblastoma.JCI insight · 2026Article
- Catalytic Proximal Protein Oligomerization as an Anti-Tumor Strategy Targeting WDR5.Nature communications · 2026Article
- WDR5 remodels NANOG condensates to drive transcriptional programs and sustain stem cell identity.Nature communications · 2026Article
- Insights into WDR5: unveiling its functions, regulation, and impact on skeletal muscle.Epigenetics · 2025Review
- 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
- RBAP48 facilitates the oral squamous cell carcinoma process in an androgen receptor-dependent and independent manners.Communications biology · 2025Article
- Crystal structures of Kif2A complexed with WDR5 reveal the structural plasticity of WIN-S7 sites.Acta biochimica et biophysica Sinica · 2025Article
- Drugging Challenging Cancer Targets Using Fragment-Based Methods.Chemical reviews · 2025Review
- WDR5 Binding to Histone Serotonylation Is Driven by an Edge-Face Aromatic Interaction with Unexpected Electrostatic Effects.Journal of the American Chemical Society · 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
- The PML1-WDR5 axis regulates H3K4me3 marks and promotes stemness of estrogen receptor-positive breast cancer.Cell death and differentiation · 2024Article
- Article
- Ribosome subunit attrition and activation of the p53-MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition.bioRxiv : the preprint server for biology · 2024Article
- Structure-Based Discovery of Potent, Orally Bioavailable Benzoxazepinone-Based WD Repeat Domain 5 Inhibitors.Journal of medicinal chemistry · 2023Article
- Discovery of Potent and Selective WDR5 Proteolysis Targeting Chimeras as Potential Therapeutics for Pancreatic Cancer.Journal of medicinal chemistry · 2023Article
- Direct mapping of ligandable tyrosines and lysines in cells with chiral sulfonyl fluoride probes.Nature chemistry · 2023Article
- Screening and optimization of phage display cyclic peptides against the WDR5 WBM site.RSC medicinal chemistry · 2023Article
- Recent Progress in Modulation of WD40-Repeat Domain 5 Protein (WDR5): Inhibitors and Degraders.Cancers · 2023Review
- WDR5 facilitates recruitment of N-MYC to conserved WDR5 gene targets in neuroblastoma cell lines.Oncogenesis · 2023Article
Corrections and comments
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Authors and funding
25 authors at 1 institution in 1 country.
Funding
Abstract
WD repeat domain 5 (WDR5) is a member of the WD40-repeat protein family that plays a critical role in multiple chromatin-centric processes. Overexpression of WDR5 correlates with a poor clinical outcome in many human cancers, and WDR5 itself has emerged as an attractive target for therapy. Most drug-discovery efforts center on the WIN site of WDR5 that is responsible for the recruitment of WDR5 to chromatin. Here, we describe discovery of a novel WDR5 WIN site antagonists containing a dihydroisoquinolinone bicyclic core using a structure-based design. These compounds exhibit picomolar binding affinity and selective concentration-dependent antiproliferative activities in sensitive MLL-fusion cell lines. Furthermore, these WDR5 WIN site binders inhibit proliferation in MYC-driven cancer cells and reduce MYC recruitment to chromatin at MYC/WDR5 co-bound genes. Thus, these molecules are useful probes to study the implication of WDR5 inhibition in cancers and serve as a potential starting point toward the discovery of anti-WDR5 therapeutics.
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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.