Development and characterization of triazole-based WDR5 inhibitors for the treatment of glioblastoma.
Overview
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
- Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, Ohio, USA
- College of Pharmacy, Korea University, Sejong, Korea
- Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, Ohio, USA
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA
- Cleveland Clinic Genome Center and
- Genomic Medicine Institute, Cleveland Clinic Research, Cleveland, Ohio, USA
- Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA
- PASS Division and
- Graudate School of Pharmaceutical Sciences, Duquesne University School of Pharmacy, Pittsburgh, Pennsylvania, USA
- Rose Ella Burkhardt Brain Tumor & Neuro-Oncology Center, Cleveland Clinic Research, Cleveland, Ohio, USA
Abstract
Glioblastoma (GBM) cancer stem cells (CSCs) contribute to tumor recurrence, treatment resistance, and dismal clinical outcomes. Genetic and pharmacological evidence suggests that the nuclear scaffolding protein WD-repeat containing protein 5 (WDR5) is a therapeutic vulnerability of the CSC population. However, previously reported WDR5 inhibitors display low permeability and are unable to penetrate the blood-brain barrier (BBB), limiting their utility in GBM. Herein, we report the structure-guided development of a series of triazole-based WDR5 WIN-site inhibitors designed to increase passive brain penetration. We identified triazole-based WDR5 inhibitors that are potent, passively permeable, and in some cases more brain penetrant than other scaffolds. We phenotypically assessed our WDR5 inhibitors in a panel of patient-derived CSC models and uncovered unique WDR5-regulated metabolic genes in GBM. We also evaluated their antiproliferative activity against CSCs both in vitro and in vivo. Finally, to identify potential combination opportunities, we screened a 2,100-compound chemical probe library and identified that the ATAD2 inhibitor BAY-850 synergizes with WDR5 inhibitors to enhance CSC killing. Our work diversifies the chemical matter targeting WDR5, clarifies the in vitro consequences of WIN-site inhibition in CSCs, and encourages the future development of next-generation WDR5 inhibitors with the potential to achieve in vivo efficacy in the brain.
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
The paper links to its data, not to its authors' code: see the Data section.
Tracing map
A tracing map links a paper to the code its authors published: this paper has none, so it has no map.
Data
Datasets cited
- geo:GSE304999, at NCBI GEO; found in “Data availability.”
Data availability
RNA-seq data associated with this manuscript have been deposited to GEO (GSE304999 (https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 2, 28 September 2026
- Authors: added Jonathan Macdonald (0000-0002-6360-2768); Feixiong Cheng (0000-0002-1736-2847); Shaun R Stauffer (0000-0002-6332-1827); removed Jonathan Macdonald; Feixiong Cheng; Shaun R Stauffer
Version 1, 28 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 24 authors, 6 keywords, 13 MeSH terms, 1 funder, 103 references.
Cite
This paper
Coker, J. A., Martinez, S. R., Han, S. H., Sloan, A. R., Gupta, A. K., Bukenya, G., Polzer, P., Ramos, J. H., Rico, E. G., Rico, A., Lindsey, A. A., Navadgi, T., Reitz, N., Romigh, T., Macdonald, J., Sonawane, D., Goins, C. M., Hubert, C. G., Wang, N. S., . . . Stauffer, S. R. (2026). Development and characterization of triazole-based WDR5 inhibitors for the treatment of glioblastoma. JCI insight, 11(12), e198298. https://
BibTeX
@article{coker2026develo
author = {Coker, Jesse A and Martinez, Steven R and Han, Sang Hoon and Sloan, Anthony R and Gupta, Amit Kumar and Bukenya, George and Polzer, Paul and Ramos, James H and Rico, Emma G and Rico, Annabella and Lindsey, A Abigail and Navadgi, Tanvi and Reitz, Natalie and Romigh, Todd and Macdonald, Jonathan and Sonawane, Dhiraj and Goins, Christopher M and Hubert, Christopher G and Wang, Nancy S and Cheng, Feixiong and Alvarado, Joseph and Sprowls, Samuel A and Lathia, Justin D and Stauffer, Shaun R},
title = {{Development and characterization of triazole-based WDR5 inhibitors for the treatment of glioblastoma}},
journal = {JCI insight},
year = {2026},
month = may,
volume = {11},
number = {12},
pages = {e198298},
publisher = {American Society for Clinical Investigation},
issn = {2379-3708},
doi = {10.1172/
url = {https://
pmid = {42084925},
pmcid = {PMC13313556}
}
RIS
TY - JOUR
AU - Coker, Jesse A
AU - Martinez, Steven R
AU - Han, Sang Hoon
AU - Sloan, Anthony R
AU - Gupta, Amit Kumar
AU - Bukenya, George
AU - Polzer, Paul
AU - Ramos, James H
AU - Rico, Emma G
AU - Rico, Annabella
AU - Lindsey, A Abigail
AU - Navadgi, Tanvi
AU - Reitz, Natalie
AU - Romigh, Todd
AU - Macdonald, Jonathan
AU - Sonawane, Dhiraj
AU - Goins, Christopher M
AU - Hubert, Christopher G
AU - Wang, Nancy S
AU - Cheng, Feixiong
AU - Alvarado, Joseph
AU - Sprowls, Samuel A
AU - Lathia, Justin D
AU - Stauffer, Shaun R
TI - Development and characterization of triazole-based WDR5 inhibitors for the treatment of glioblastoma
T2 - JCI insight
J2 - JCI Insight
PY - 2026
DA - 2026/
VL - 11
IS - 12
SP - e198298
SN - 2379-3708
PB - American Society for Clinical Investigation
DO - 10.1172/
UR - https://
LA - en
ER -
CSL-JSON
{
"id": "10.1172/
"type": "article-journal",
"title": "Development and characterization of triazole-based WDR5 inhibitors for the treatment of glioblastoma",
"container-title": "JCI insight",
"author": [
{
"family": "Coker",
"given": "Jesse A"
},
{
"family": "Martinez",
"given": "Steven R"
},
{
"family": "Han",
"given": "Sang Hoon"
},
{
"family": "Sloan",
"given": "Anthony R"
},
{
"family": "Gupta",
"given": "Amit Kumar"
},
{
"family": "Bukenya",
"given": "George"
},
{
"family": "Polzer",
"given": "Paul"
},
{
"family": "Ramos",
"given": "James H"
},
{
"family": "Rico",
"given": "Emma G"
},
{
"family": "Rico",
"given": "Annabella"
},
{
"family": "Lindsey",
"given": "A Abigail"
},
{
"family": "Navadgi",
"given": "Tanvi"
},
{
"family": "Reitz",
"given": "Natalie"
},
{
"family": "Romigh",
"given": "Todd"
},
{
"family": "Macdonald",
"given": "Jonathan"
},
{
"family": "Sonawane",
"given": "Dhiraj"
},
{
"family": "Goins",
"given": "Christopher M"
},
{
"family": "Hubert",
"given": "Christopher G"
},
{
"family": "Wang",
"given": "Nancy S"
},
{
"family": "Cheng",
"given": "Feixiong"
},
{
"family": "Alvarado",
"given": "Joseph"
},
{
"family": "Sprowls",
"given": "Samuel A"
},
{
"family": "Lathia",
"given": "Justin D"
},
{
"family": "Stauffer",
"given": "Shaun R"
}
],
"container-title-short":
"volume": "11",
"issue": "12",
"page": "e198298",
"DOI": "10.1172/
"PMID": "42084925",
"PMCID": "PMC13313556",
"ISSN": "2379-3708",
"publisher": "American Society for Clinical Investigation",
"URL": "https://
"language": "en",
"issued": {
"date-parts": [
[
2026,
5,
5
]
]
}
}
Similar papers
The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.
- [1] doi:10.1016/j.stemcr.2026.103013
- Targeting mitotic kinesin KIF20A: A differentiation-based therapeutic strategy for glioblastoma stem/
progenitor cells. Journal: Stem cell reportsIn common: other condition, mouse, 4 references - [2] doi:10.1016/j.celrep.2026.117408
- NAT10-dependent N&
lt;sup& gt;4& lt;/ sup& gt;-acetylcytidine reprograms R-loops and promotes cancer stem cell growth. Journal: Cell reportsIn common: other condition, mouse, 3 references - [3] doi:10.1021/acs.jmedchem.6c00035
- The Discovery of TNG456: A Highly Potent, Selective, Brain-Penetrant MTA-Cooperative PRMT5 Inhibitor for the Treatment of &
lt;i& gt;MTAP& lt;/ i& gt;-Deleted Cancers. Journal: Journal of medicinal chemistryIn common: other condition, mouse, 3 references - [4] doi:10.1002/advs.76205 [code]
- CHCHD10 Mitigates Alzheimer's Disease-Related Phenotypes in Association With Epigenetic Remodeling in Directly Reprogrammed Neurons.Journal: Advanced science (Weinheim, Baden-Wurttemberg, Germany)In common: author Feixiong Cheng
- [5] doi:10.1021/acs.jmedchem.6c01461
- Dual Inhibitors of p38α Mitogen-Activated Protein Kinase and Butyrylcholinesterase for the Modulation of Neuroinflammation and Cognitive Dysfunction.Journal: Journal of medicinal chemistryIn common: mouse, 3 references
- [6] doi:10.1021/acsomega.6c01637 [code]
- Exploring the Interactive Effect of Pectins from &
lt;i& gt;Campomanesia xanthocarpa& lt;/ i& gt; with Galectin‑3. Journal: ACS omegaIn common: other condition, 3 references - [7] doi:10.1016/j.stemcr.2026.103012
- Identification of novel genes with enriched expression in human intermediate progenitors reveals a key role for CDKN3 in cortical development.Journal: Stem cell reportsIn common: mouse, 3 references
- [8] doi:10.1186/s11689-026-09713-0 [code]
- DRP1 mutations associated with EMPF1 encephalopathy perturb the transcriptional profile and maturation of cortical neurons.Journal: Journal of neurodevelopmental disordersIn common: other condition, 4 references
- [9] doi:10.1038/s41467-026-74153-2 [code]
- Regional, functional and transcriptomic decoding of multidimensional brain structure alterations in obsessive-compulsive disorder.Journal: Nature communicationsIn common: other condition, 4 references
- [10] doi:10.1016/j.stemcr.2026.102930 [code]
- ZFHX4 is necessary for dopaminergic neuron differentiation and controls cell cycle by regulating LIN28A.Journal: Stem cell reportsIn common: 4 references
Contribute
The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.
Sign in with ORCID to claim this paper as one of its authors, correct its record or validate its tracing map: when the paper's metadata lists your ORCID iD, you are recognized at once. Maintainers of its code: sign in with GitHub, then claim the repository on your account page.
Claim this paper
Correct its record
Say what each link of this record is, remove the ones that are not the paper's, add the ones that are missing. The correction becomes a new version of the record, in its Versions section.
Request its removal
To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).
Discussion, reproductions, activity
Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.
Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.
Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.