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Publications

Journal Article Ahead of print 1 citation

PubMed: 42839082 DOI: 10.1038/s41589-026-02306-x

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

Nat Chem Biol

Authors: 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, Karen Tran, Chloe Shard, Guillermo A Gomez, Ashwini Patil, Diana D Shi, Julie-Aurore Losman, Angus J Saxton, Jennifer R Baker, Zhihe Lei, Matthew T O Holland, Paul E Brennan, Mathias Francois, Andreas Kraemer, Susanne Mueller, Yuchen Feng, Paul Workman, Lenka Munoz

Affiliations

  • School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
  • Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia.
  • School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney, New South Wales, Australia.
  • Centre for Child Health Research, Medical School, University of Western Australia, Crawley, Western Australia, Australia.
  • Cancer Centre, Telethon Kids Institute, Nedlands, Western Australia, Australia.
  • Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, Australia.
  • School of Clinical Medicine, University of New South Wales, Sydney, New South Wales, Australia.
  • Centre for Cancer Biology, Adelaide University, Adelaide, South Australia, Australia.
  • Combinatics, 2-2-6 Sugano, Ichikawa-shi, Chiba, Japan.
  • Department of Radiation OncologyMass General Brigham, Harvard Medical School, Boston, MA, USA.
  • Krantz Family Cener for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
  • Department of Medical Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Discipline of Chemistry, School of Science, The University of Newcastle, Callaghan, New South Wales, Australia.
  • School of Science, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales, Australia.
  • Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt am Main, Germany.
  • Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Frankfurt am Main, Germany.
  • Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany.
  • Chemical Probes Portal, London, UK.
  • Centre for Cancer Drug Discovery, Division of Cancer Therapeutics, Institute of Cancer Research, London, UK.
  • School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
  • Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia.

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.

MeSH

Cells, Microscopy, Electron, Scanning Transmission, Neoplasms, Stem Cells, Enzymes, Glioblastoma