Evidence map›Paper›PMID 42839082›Full record

ArticleNature chemical biology2026

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

Jayden R Sterling, Jacinda R Holtsmark, George L Joun, Matthew S Graus, Tian Y Du, Mani Kuchibhotla, Terrance G Johns, Antoine deWeck, Lipin Loo, G Gregory Neely and 17 more

Abstract read
PubMed Publisher
In one paragraph

Article in Nature chemical biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

27 authors.

Jayden R Sterling *School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
Jacinda R Holtsmark *School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
George L JounSchool of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
Matthew S GrausSchool of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0001-5470-4837
Tian Y DuCharles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0002-0674-361X
Mani KuchibhotlaCentre for Child Health Research, Medical School, University of Western Australia, Crawley, Western Australia, Australia.
Terrance G JohnsCentre for Child Health Research, Medical School, University of Western Australia, Crawley, Western Australia, Australia.ORCID http://orcid.org/0000-0002-8874-4543
Antoine deWeckChildren's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, Australia.
Lipin LooCharles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia.
G Gregory NeelyCharles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0002-1957-9732
Karen TranSchool of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.ORCID http://orcid.org/0009-0000-4703-6658
Chloe ShardCentre for Cancer Biology, Adelaide University, Adelaide, South Australia, Australia.ORCID http://orcid.org/0000-0002-7408-9269
Guillermo A GomezCentre for Cancer Biology, Adelaide University, Adelaide, South Australia, Australia.ORCID http://orcid.org/0000-0002-0494-2404
Ashwini PatilCombinatics, 2-2-6 Sugano, Ichikawa-shi, Chiba, Japan.ORCID http://orcid.org/0000-0002-3353-1970
Diana D ShiDepartment of Radiation OncologyMass General Brigham, Harvard Medical School, Boston, MA, USA.
Julie-Aurore LosmanDepartment of Medical Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA.
Angus J SaxtonDiscipline of Chemistry, School of Science, The University of Newcastle, Callaghan, New South Wales, Australia.ORCID http://orcid.org/0009-0004-1179-099X
Jennifer R BakerSchool of Science, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales, Australia.
Zhihe LeiCentre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0001-9614-9886
Matthew T O HollandCentre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0003-2322-4384
Paul E BrennanCentre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Mathias FrancoisSchool of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0002-9846-6882
Andreas KraemerInstitute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt am Main, Germany.ORCID http://orcid.org/0000-0003-3294-2660
Susanne MuellerInstitute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt am Main, Germany.ORCID http://orcid.org/0000-0003-2402-4157
Yuchen FengSchool of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0001-5507-8129
Paul WorkmanChemical Probes Portal, London, UK.ORCID http://orcid.org/0000-0003-1659-3034
Lenka MunozSchool of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia. lenka.munoz@sydney.edu.au.ORCID http://orcid.org/0000-0002-7625-5646

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Histone lysine demethylase 4 (KDM4) enzymes are frequently overexpressed in cancer and are considered to be promising therapeutic targets. QC6352, which is widely used as a best-in-class KDM4 chemical probe, shows potent antitumor activity across cancer models. Using comprehensive chemical biology approaches in glioblastoma models, we demonstrate that the efficacy of QC6352 and that of its clinical analog zavondemstat are independent of KDM4 inhibition. Instead, we identify dihydroorotate dehydrogenase (DHODH), a key enzyme in de novo pyrimidine biosynthesis, as the functional target driving their antiproliferative activity. Uridine supplementation and expression of an inhibitor-resistant DHODH mutant fully abrogate growth inhibition, whereas the orthogonal KDM4 inhibitor ML324, which lacks DHODH inhibition, fails to phenocopy QC6352. These findings establish QC6352 and zavondemstat as dual KDM4-DHODH inhibitors and identify DHODH inhibition as the dominant driver of their antiglioblastoma efficacy, as well as demonstrating the need for orthogonal chemical probes to accurately define drug mechanisms in cells.

Identifiers

PMID42839082

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.