Scientists thought they knew how this 70-year-old leukemia drug worked — SkimNews
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- 6-thioguanine (6-TG) has treated leukemia for over 70 years, but researchers at CeMM, the University of Oxford, the Weizmann Institute, and the University of Dundee found that cells were protected from the drug when NUDT5 was removed — even though blocking NUDT5's enzymatic activity had little effect.
- NUDT5 influences 6-TG sensitivity through a non-catalytic mechanism — the protein acts as a molecular scaffold that helps organize cellular metabolism, a function separate from its enzymatic role that researchers discovered in earlier 2025 work published in Science.
- dNUDT5, a compound developed through targeted protein degradation by the Huber laboratory at Oxford, eliminates NUDT5 from cells rather than merely inhibiting it, exposing biology that conventional enzyme inhibitors miss.
- NUDT5 and NUDT15 appear to have opposing effects on thiopurine response: loss of NUDT15 makes cells more sensitive to 6-TG, while reducing NUDT5 makes cells more resistant — suggesting the two proteins push cells in opposite directions through different mechanisms.
- Targeted protein degradation is highlighted in the Nature Communications paper as a tool to separate what a protein does as an enzyme from what it does as a physical presence in the cell, enabling the discovery of hidden drug-response mechanisms.
- The findings do not immediately yield a new treatment but could help explain why patients respond differently to thiopurine drugs, with funding from the ERC, Austrian Science Fund, Vienna Science and Technology Fund, and the Wellcome Trust.
Why it matters: The discovery gives drug developers a new lens on why leukemia patients respond differently to thiopurines — a drug class in clinical use since the 1950s — by showing that protein presence, not just enzymatic activity, can determine drug sensitivity. It also validates targeted protein degradation as a discovery tool that exposes biology invisible to conventional inhibitors, potentially reshaping how researchers approach enzyme-targeted drug discovery.
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