A medicinal chemistry program at the University of Oxford, led by Professor Kilian Huber, produced a set of selective NUDT5 degraders. The lead compound, called dNUDT5, eliminated the protein from cells. The team also made matched control molecules that bind to NUDT5 without triggering its destruction.

"Chemical degraders give us a way to separate what a protein does as an enzyme from what it does as a physical presence in the cell," says Huber, co-corresponding author of the study. "In this case, that distinction was decisive: removing NUDT5 revealed biology that conventional inhibitors missed."

Co-first author Anne-Sophie Marques described the discovery pipeline. "We developed a cell-based platform to accelerate the discovery of NUDT5 degraders. This platform helped guide the medicinal chemistry efforts that ultimately produced dNUDT5, our most active degrader."

When the team compared dNUDT5 with conventional NUDT5 inhibitors, the difference was striking. Enzyme inhibitors left the cellular response to 6-TG largely unchanged. dNUDT5, by contrast, shielded cells from the drug's toxic effects in a clear, dose-dependent manner. Genetic experiments that deleted the NUDT5 gene produced the same result.

What was the initial assumption, and what broke it?

"We initially expected that NUDT5 would influence 6-TG through its enzymatic activity," says co-first author Tuan-Anh Nguyen from CeMM. "Instead, we found that inhibiting the enzyme had little effect. What mattered was whether the protein itself was present."

Co-first author Ludwig Bauer recalled the moment the trend emerged. "As the results came in, it became immediately clear that dNUDT5 was protecting cells from 6-thioguanine toxicity in a dose-dependent manner. That was an incredibly exciting moment."

How does NUDT5 relate to the better-known protein NUDT15?

The team also examined NUDT15, a protein clinicians already link to patient response to thiopurine drugs. The two proteins push cells in opposite directions:

• Loss of NUDT15 makes cells more sensitive to 6-TG.
• Loss of NUDT5 makes cells more resistant to 6-TG.

The opposing effects suggest the two proteins influence thiopurine response through distinct mechanisms, not a shared one. Researchers can now ask whether measuring both proteins might eventually help predict which patients will respond to treatment.

What does this change for patients today?

The work does not yet change clinical practice. No new drug has emerged from the study, and the experiments were performed in cells, not in people. The research does, however, offer a mechanistic explanation for variability in patient responses to a long-used therapy.

The result also validates targeted protein degradation as a discovery tool. Conventional enzyme inhibitors can miss functions that depend on a protein's physical presence rather than its chemistry, and degrader-based studies may now join the standard toolkit for thiopurine research.

The study received funding from the European Research Council, the Austrian Science Fund, the Vienna Science and Technology Fund, the Marie Skłodowska-Curie Actions program, the Innovative Medicines Initiative 2 Joint Undertaking, the Wellcome Trust, Merck Sharp & Dohme Corp. and Janssen Pharmaceutica NV.