A paper titled "DHODH is the key target of the KDM4 inhibitor QC6352 in glioblastoma stem cells," published October 6, 2026, in Nature Chemical Biology, was led by Lenka Munoz of the University of Sydney, according to the university's press release. The finding has direct implications for how prior research using QC6352 as a KDM4 probe should be interpreted, and for the ongoing clinical evaluation of zavondemstat.
The biochemical potency difference is substantial: the R-forms of QC6352 and zavondemstat inhibit DHODH with IC50 values of 0.3 nM and 0.6 nM, respectively, compared with KDM4A IC50 values of 355 nM and 767 nM — roughly a 1,000-fold difference between the two targets. DHODH (dihydroorotate dehydrogenase) catalyzes the conversion of dihydroorotate to orotate in de novo pyrimidine biosynthesis, which supplies nucleotides for DNA, RNA and lipid synthesis, and blocking it depletes cells of uridine nucleotides.
The authors used several approaches to test whether DHODH is the functional target: adding uridine, which feeds the nucleotide salvage pathway, fully reversed the growth arrest caused by QC6352 and zavondemstat in glioblastoma models, and overexpressing the inhibitor-resistant DHODH A58T mutant strongly rescued growth in the presence of both compounds. By contrast, ML324, a KDM4 inhibitor with KDM4A potency comparable to QC6352 but no DHODH inhibition, did not reproduce QC6352's antiproliferative effects, and individual knockout of KDM4A, KDM4B, and KDM4C did not change sensitivity to QC6352. In metabolomic profiling, dihydroorotate and carbamoylaspartate accumulated while UMP, UDP, and UTP were depleted, a pattern that matched the DHODH inhibitor BAY2402234, and a 1.95 Å cocrystal structure of human DHODH bound to QC6352 showed the compound's hydrophobic tail in the tunnel normally used by the cofactor ubiquinone.
Zavondemstat, a clinical analog of QC6352 previously developed as a KDM4 inhibitor by Tachyon Therapeutics, entered a Phase I study (NCT05076552) in advanced solid tumors. Thirty patients were treated across six dose cohorts before the sponsor discontinued further study enrollment for business reasons. The maximum tolerated dose was not reached and a recommended Phase II dose was not established, with the first-in-human results reported in 2025.
The new study suggests that zavondemstat’s biological activity may need to be interpreted through its much more potent inhibition of DHODH rather than KDM4 alone. The paper's authors state that the KDM4-independent mechanism "does not preclude potential clinical benefits of zavondemstat" and say that ongoing and future zavondemstat trials should be benchmarked against earlier DHODH inhibitor studies.