DHODH is the key target of the KDM4 inhibitor QC6352 in glioblastoma stem cells.

DHODH inhibition, not KDM4 suppression, drives the anti-glioblastoma activity of QC6352 and zavondemstat, with DHODH as the key target in glioblastoma stem cells.

• Why it matters: Understanding the true mechanism of these compounds is crucial for developing effective therapies, as previous assumptions about KDM4 targeting may be misleading in cancer treatment.
• What they did: Researchers used chemical biology approaches in glioblastoma models to show that QC6352 and zavondemstat act primarily through DHODH inhibition, not KDM4, with 100% of growth inhibition reversed by uridine or resistant DHODH mutants.
• The result: This work redefines the drugs' mechanisms, highlighting DHODH as a promising therapeutic target and emphasizing the importance of orthogonal probes to accurately determine drug actions in cancer cells.