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

  • JCI Insight. 2026 May 5;11(12):e198298. doi: 10.1172/jci.insight.198298.
Jesse A Coker  1  2 ,  Steven R Martinez  2 ,  Sang Hoon Han  2  3 ,  Anthony R Sloan  4  5 ,  Amit Kumar Gupta  6  7 ,  George Bukenya  4 ,  Paul Polzer  2 ,  James H Ramos  4 ,  Emma G Rico  2 ,  Annabella Rico  2 ,  A Abigail Lindsey  2 ,  Tanvi Navadgi  4 ,  Natalie Reitz  4 ,  Todd Romigh  2 ,  Jonathan Macdonald  2 ,  Dhiraj Sonawane  2 ,  Christopher M Goins  1  2 ,  Christopher G Hubert  5  8 ,  Nancy S Wang  2 ,  Feixiong Cheng  1  5  6  7 ,  Joseph Alvarado  1  2 ,  Samuel A Sprowls  9  10 ,  Justin D Lathia  4  5  11 ,  Shaun R Stauffer  1  2
Affiliations
  • 1. Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.
  • 2. Cleveland Clinic Center for Therapeutics Discovery (C3TD), Cleveland Clinic Research, Cleveland, Ohio, USA.
  • 3. College of Pharmacy, Korea University, Sejong, Korea.
  • 4. Department of Cardiovascular Medicine, Cleveland Clinic Research, Cleveland, Ohio, USA.
  • 5. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA.
  • 6. Cleveland Clinic Genome Center and.
  • 7. Genomic Medicine Institute, Cleveland Clinic Research, Cleveland, Ohio, USA.
  • 8. Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA.
  • 9. PASS Division and.
  • 10. Graudate School of Pharmaceutical Sciences, Duquesne University School of Pharmacy, Pittsburgh, Pennsylvania, USA.
  • 11. Rose Ella Burkhardt Brain Tumor & Neuro-Oncology Center, Cleveland Clinic Research, Cleveland, Ohio, USA.
PMID: 42084925 DOI: 10.1172/jci.insight.198298
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.

Keywords
Brain cancer; Cell biology; Neuroscience; Oncology; Structural biology; Therapeutics.
Products