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ResearchIn-Press PreviewCell biologyNeuroscienceOncology Open Access | 10.1172/jci.insight.198298

Development and characterization of triazole-based WDR5 inhibitors for the treatment of glioblastoma

Jesse A. Coker,1 Steven R. Martinez,2 Sang Hoon Han,2 Anthony R. Sloan,3 Amit Kumar Gupta,4 George Bukenya,3 Paul Polzer,2 James H. Ramos,3 Emma G. Rico,2 Annabella Rico,2 A. Abigail Lindsey,2 Tanvi Navadgi,3 Natalie Reitz,3 Todd Romigh,2 Jonathan Macdonald,2 Dhiraj Sonawane,2 Christopher M. Goins,1 Christopher G. Hubert,5 Nancy S. Wang,2 Feixiong Cheng,1 Joseph Alvarado,1 Samuel A. Sprowls,6 Justin D. Lathia,3 and Shaun R Stauffer1

1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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1Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United States of America

2Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, United States of America

3Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, United States of America

4Cleveland Clinic Genome Center, Cleveland Clinic Research, Cleveland, United States of America

5Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States of America

6PASS Division, Duquesne University School of Pharmacy, Pittsburgh, United States of America

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Published May 5, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.198298.
Copyright © 2026, Coker et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 5, 2026 - Version history
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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 novel 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 novel 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 novel 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.

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  • Version 1 (May 5, 2026): In-Press Preview
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