A leukemia drug doctors have trusted since the 1950s turns out to fight cancer in a way nobody expected, and the discovery could rewrite how scientists design cancer treatments.
Quick Take
- A new study finds a decades-old leukemia drug called 6-thioguanine works through a protein’s physical presence, not its chemical activity.
- Researchers thought a protein called NUDT5 helped the drug work by acting as an enzyme, a tiny chemical machine.
- Removing NUDT5 protected cells from the drug’s toxic effects, but blocking its enzyme function did almost nothing.
- Scientists say NUDT5 instead acts like a scaffold, holding another protein in place to control how the drug kills cancer cells.
An Old Drug Gets a New Explanation
Doctors have used 6-thioguanine, known as 6-TG, to treat leukemia for roughly 70 years. It works by slipping into a cancer cell’s DNA-building machinery and gumming up the process, killing the cell. For years, scientists believed a protein called NUDT5 played a supporting role in that process by acting as an enzyme, a molecule that speeds up chemical reactions inside cells.
A study published in Nature Communications in 2026 challenges that idea directly. Researchers used a technique called targeted protein degradation, which lets scientists erase a protein from a cell entirely instead of just blocking its chemical function. That distinction turned out to matter enormously for understanding how the old drug actually works.
When the team blocked NUDT5’s enzyme activity with a chemical inhibitor, cells responded to 6-TG almost the same as before. Nothing much changed. But when researchers removed the NUDT5 protein completely from the cells, something different happened. The cells became protected from the drug’s toxic effects.
The Protein Was Never Just a Chemical Machine
That result flips a basic assumption. If NUDT5 helped the drug work purely through its enzyme function, blocking that function should have produced the same protective effect as removing the protein outright. It did not. Researchers now describe NUDT5’s role in drug sensitivity as having “nothing to do with its enzymatic activity,” according to coverage from the University of Oxford.
Instead, scientists believe NUDT5 acts more like a scaffold, a structural piece that holds other proteins in position rather than driving a chemical reaction itself. Earlier work from the same research groups pointed to a specific partner: a protein called phosphoribosyl pyrophosphate amidotransferase (PPAT), which controls how cells build new purines, the molecular building blocks of DNA and RNA.
According to that earlier research, NUDT5 binds to PPAT and organizes it into clusters, which suppresses how much new purine material the cell can produce. That suppression pushes cells to rely on the same salvage pathway that 6-TG hijacks, making the drug’s toxic chemical building block more likely to get built into damaged DNA. Losing NUDT5 breaks that whole arrangement, letting cells sidestep the drug’s attack.
Why This Distinction Actually Matters
This is not a small technical footnote. Drug companies build cancer treatments around specific targets, often designing chemicals meant to switch a protein’s enzyme activity off. If a protein’s real importance lies in simply being present and organizing other molecules, an activity-blocking drug could fail even when the target itself is genuinely important to the disease.
Researchers behind the work say the findings reveal “a novel and unexpected, non-enzymatic role” for NUDT5 in how cells respond to thiopurine drugs like 6-TG, based on gene-editing experiments and a custom-built protein-degrading compound. That combination of tools, rather than a single test, gives the conclusion added weight, even though the fully published dataset and detailed methods were not all available for outside review at time of writing.
This finding fits a broader pattern researchers have noticed across biology. Many proteins first understood purely as chemical catalysts later turn out to moonlight as structural organizers, and removing a protein entirely often reveals functions that chemical inhibitors simply cannot touch. Thiopurine drugs in particular have a long history of mechanistic surprises, since the pathway involves multiple enzymes working together rather than one clean target.
For patients, the practical treatment does not change today. Doctors will keep prescribing 6-thioguanine the way they always have. But for the scientists designing tomorrow’s cancer drugs, the lesson lands hard: sometimes a protein’s job has nothing to do with what it chemically does, and everything to do with simply being in the room.
Sources:
sciencedaily.com, ndm.ox.ac.uk
