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Tuan-Anh Nguyen / Wolfgang Däuble
Published in Nature Communications (DOI 10.1038/s41467-026-74489-9), the findings combine targeted protein degradation, medicinal chemistry and genetic experiments to uncover a previously hidden layer of thiopurine biology and further challenge traditional views of how enzymes function in cells.
For more than 70 years, the drug 6-thioguanine (6-TG) has been used to treat leukemia. Although its clinical effects have been studied extensively, scientists are still uncovering the molecular mechanisms that determine whether cells succumb to the drug or survive its attack.
Now, researchers at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, together with collaborators at the University of Oxford, the Weizmann Institute of Science and the University of Dundee, have identified an unexpected player in this process: the protein NUDT5.
The discovery builds directly on a recent breakthrough from the Kubicek and Huber laboratories (Science, 2025). In that work, researchers showed that NUDT5 performs a critical cellular function independently of its enzymatic activity. Instead of acting primarily as a catalyst, NUDT5 was found to serve as a molecular scaffold that helps organize cellular metabolism. This unusual behavior has direct consequences for the action of the important cancer drug.
Read the full story on the Nuffield Department of Medicine website.