Cancer Drug’s Real Target Surprises Researchers in Glioblastoma Study
Researchers report that the experimental cancer drug zavondemstat and related compound QC6352 mainly inhibit DHODH rather than KDM4, the target they were designed to block. The finding came from tests against glioblastoma using patient-derived stem cells and tumor models. Because DHODH helps supply DNA building blocks, the unexpected mechanism may require rethinking earlier studies of these compounds.
Zavondemstat and QC6352 were designed to hit KDM4 proteins, which can help cancer cells grow and spread when overactive. In glioblastoma research, other KDM4 inhibitors did not reproduce QC6352’s anticancer effects, suggesting the compound was working through a different route.
Using stem cells obtained from glioblastoma patients and tumor models, the team attributed most activity to DHODH inhibition. DHODH helps supply materials for making DNA. The researchers also created compounds that block KDM4 but not DHODH, giving scientists a way to separate the two mechanisms. The study involved several institutions and appeared in Nature Chemical Biology.
The findings could influence how researchers interpret past KDM4 studies and how future glioblastoma trials are designed. Patients with this aggressive brain cancer may eventually benefit if DHODH-targeting drugs are tested, though current evidence comes only from cells and tumor models. Drug developers and clinical teams may need to reassess assumptions about zavondemstat’s mechanism, which could affect patient selection and research priorities.