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

Area of Science:

• Oncology
• Medicinal Chemistry
• Neuroscience

Background:

• Glioblastoma (GBM) cancer stem cells (CSCs) drive tumor recurrence and treatment resistance.
• WD-repeat containing protein 5 (WDR5) is a therapeutic target in CSCs, but existing inhibitors lack blood-brain barrier (BBB) penetration.

Purpose of the Study:

• To develop novel WDR5 inhibitors with enhanced passive brain penetration for GBM treatment.
• To evaluate the efficacy and identify synergistic combinations for WDR5 inhibitors in CSC models.

Main Methods:

• Structure-guided design of novel triazole-based WDR5 WIN-site inhibitors.
• Assessment of inhibitor potency, passive permeability, and BBB penetration.
• Phenotypic and antiproliferative evaluation in patient-derived CSC models (in vitro and in vivo).
• Chemical probe library screening for synergistic drug combinations.

Main Results:

• Identified potent, passively permeable triazole-based WDR5 inhibitors with improved brain penetration.
• Uncovered unique WDR5-regulated metabolic genes in GBM CSCs.
• Demonstrated antiproliferative activity of novel WDR5 inhibitors against CSCs.
• Discovered synergistic killing of CSCs when WDR5 inhibitors are combined with ATAD2 inhibitor BAY-850.

Conclusions:

• Novel triazole-based WDR5 inhibitors offer a promising chemical scaffold for targeting GBM CSCs.
• These inhibitors exhibit enhanced brain penetration, addressing a key limitation of previous WDR5-targeting agents.
• Combination therapy with WDR5 and ATAD2 inhibitors shows potential for enhanced CSC killing, warranting further investigation for in vivo efficacy.