6‑Thioguanine Reveals Hidden Role of NUDT5 in Leukemia

A 70‑year‑old leukemia drug, 6‑thioguanine, has been found to interact with the protein NUDT5 in a way that affects cancer cell survival. Researchers discovered that removing NUDT5, rather than just inhibiting its enzyme function, makes cells more resistant to the drug, revealing a previously hidde…

By Felo News Desk · Published Sat, 19 Sep 2026 02:48:41 GMT

For more than seven decades, the chemotherapy agent 6‑thioguanine (6‑TG) has been a staple in treating leukemia, a disease of the blood‑forming tissues. Despite its long history, scientists are still learning why some cancer cells survive the drug while others are killed. Recent research from a collaboration between the CeMM Research Center, the University of Oxford, the Weizmann Institute of Science, and the University of Dundee has shed new light on this mystery, pointing to the protein NUDT5 as a key player.

NUDT5’s Unexpected Role in Drug Response

Proteins are typically understood by the chemical reactions they catalyze. Drugs often target these enzymatic activities. However, NUDT5 appears to do more than just act as an enzyme. Earlier work published in Science in 2025 showed that NUDT5 can also function as a molecular scaffold, physically binding to PPAT—a protein involved in purine synthesis, the building blocks of DNA and RNA. By restraining PPAT, NUDT5 limits the cell’s production of purines, which is crucial because 6‑TG is an antimetabolite that must be metabolically activated inside cells to interfere with normal cellular processes.

In the new study, researchers expected that blocking NUDT5’s enzymatic activity would alter the cell’s response to 6‑TG. Instead, they found that simply inhibiting the enzyme had little effect. What mattered was whether the NUDT5 protein itself was present in the cell.

Targeted Protein Degradation Uncovers Hidden Biology

To separate the catalytic function from other roles, the team employed targeted protein degradation—a technique that removes the entire protein from the cell rather than just turning off its active site. At Oxford, a team of medicinal chemists developed a series of highly selective molecules that could degrade NUDT5, along with matched compounds that bound the protein without destroying it. These degraders were compared to conventional NUDT5 inhibitors in a cell‑based platform designed to accelerate discovery.

The results were striking. Degrading NUDT5 made leukemia cells more resistant to 6‑TG, while inhibiting its enzymatic activity had no significant impact. Genetic experiments that knocked out NUDT5 confirmed the same pattern, indicating that the protein’s physical presence—not its catalytic activity—dictates how cells respond to the drug.

NUDT5 vs. NUDT15: Opposing Effects

Another protein, NUDT15, shares a similar name and is already known to influence thiopurine drug responses. NUDT15 helps break down active metabolites of 6‑TG, so loss of NUDT15 makes cells more sensitive to the drug. In contrast, loss of NUDT5 confers resistance. This opposite behavior suggests that the two proteins operate through distinct biological pathways rather than as interchangeable members of the same metabolic circuit.

The earlier Science study provides a possible framework: NUDT5’s interaction with PPAT restrains purine production. Removing this restraint could increase purine synthesis, altering the metabolic environment in which thiopurine drugs act. The new findings reinforce the idea that a protein’s structural or scaffolding roles can be as important as its enzymatic functions.

Implications for Cancer Treatment

While the study does not immediately change clinical practice, it deepens our understanding of how 6‑TG works and why patient responses vary. By revealing a hidden layer of biology, the research opens the door to new biomarkers that could predict which patients will benefit most from thiopurine therapy. Future investigations may explore whether targeting NUDT5’s scaffolding function could enhance drug efficacy or overcome resistance.

The work was published in Nature Communications on 30 June 2026 and was supported by a range of European and international funding bodies, including the European Research Council, the Austrian Science Fund, the Wellcome Trust, and pharmaceutical companies such as Merck and Janssen Pharmaceutica.

In summary, the discovery that NUDT5’s physical presence—not its enzymatic activity—determines leukemia cell sensitivity to 6‑TG highlights the importance of considering non‑catalytic protein functions in drug development and cancer biology.

Key facts

6‑TG’s effectiveness depends on NUDT5’s presence, not its enzyme activity
Targeted protein degradation revealed hidden biological functions
NUDT5 and NUDT15 have opposing effects on thiopurine sensitivity
The study suggests new biomarkers for predicting drug response
No immediate change to clinical practice, but opens avenues for future research

Why it matters

Understanding that a protein’s structural role can influence chemotherapy response helps explain why some patients tolerate or resist treatment, potentially guiding personalized therapy strategies.

Frequently asked questions

What is 6‑thioguanine used for?

6‑Thioguanine is an antimetabolite chemotherapy drug used primarily to treat various forms of leukemia by interfering with DNA and RNA synthesis.

How does NUDT5 normally function in cells?

NUDT5 is an enzyme that can also act as a molecular scaffold, binding to PPAT to regulate purine synthesis, which is essential for DNA and RNA production.

Why does removing NUDT5 make cells resistant to 6‑TG?

The removal of NUDT5 lifts its restraint on purine synthesis, potentially altering the metabolic environment and reducing the drug’s effectiveness.

Does this research change how doctors prescribe 6‑TG today?

Not yet. The findings are mechanistic and do not yet translate into new treatment protocols, but they may inform future personalized medicine approaches.