Discovery reveals ‘handbrake’ that controls cancer drug response

A world-first discovery, published in the journal Science, rewrites our understanding of how cells control the production of DNA’s building blocks - and how this process affects the response to widely used cancer and autoimmune drugs.

The study, led by researchers from the University of Oxford in collaboration with scientists from the CeMM (Research Centre for Molecular Medicine), Austria focused on the enzyme NUDT5, known to have a role in cellular energy metabolism and signalling. This new work uncovered a previously unknown function where NUDT5 acts as a molecular ‘handbrake’ on another enzyme, PPAT, which controls the rate of purine synthesis - the pathway that generates a key building block for DNA and RNA base pairs. By restraining PPAT, NUDT5 fine-tunes the cell’s nucleotide supply, limiting DNA replication.

When this ‘handbrake’ is lost - through genetic variation, disease, or chemical removal - cells overproduce purines. These purines can out-compete certain cancer drug treatments that mimic these molecules (such as thiopurines), thus rendering the treatment ineffective. This discovery helps explain why some patients respond better than others to long-used drugs such as 6-thioguanine, used in leukaemia and autoimmune disease.

This study builds on previous work from the Oxford team and others showing that NUDT5 can be targeted by drug-like small molecules, opening the door to probe its biological roles in cells.

To investigate its function, the Oxford team developed dNUDT5, a first-in-class small-molecule degrader that removes NUDT5 entirely from cultured human cells. Unlike traditional enzyme blockers, this approach revealed that the protein also acts as a scaffold, tightly binding and thus inhibiting PPAT, the key enzyme required for purine production. Removing NUDT5 abolished the brake on purine synthesis and provided direct evidence of the mechanism.

Using proteomics, the researchers then discovered that NUDT5 physically interacts with PPAT, explaining how this enzyme can control metabolism through structure rather than chemistry. Additionally, researchers found that dNUDT5 could rescue adenosine-induced toxicity in patient-derived fibroblasts from individuals with MTHFD1 deficiency, showing the pathway’s broader biomedical relevance.

'This discovery was a big surprise, in the best possible way,' said Professor Kilian Huber, who led the work from Oxford’s Centre for Medicines Discovery, part of the Nuffield Department of Medicine. 'An enzyme long thought to have a single, well-defined role turned out to moonlight as a molecular scaffold - something never seen before in this enzyme family.  It challenges the textbook view of how cells regulate the production of DNA building blocks and offers a fundamental insight into cellular control. It’s also a reminder that in science, you should never take anything for granted - even familiar proteins can still surprise us. This work shows what can be achieved when curiosity-driven research meets international collaboration.

'Our team is now evaluating NUDT5-PPAT as a potential biomarker in clinical samples, advancing NUDT5 degraders through preclinical testing, and exploring whether other enzymes might have similar hidden scaffold roles in cell metabolism.'

Dr Anne-Sophie Marques, co-first author on the study, said: 'In this study we have shown an unprecedented role of NUDT5 in repressing the purine de novo biosynthetic pathway. In addition to proving that the scaffolding role of NUDT5 is essential in this phenotype, we have demonstrated that the interaction between NUDT5 and PPAT, the rate-limiting enzyme of purine de novo synthesis, acts like a switch to repress the pathway.

'It is undeniable that our results pave the way for future discoveries around the NUDT5 protein and its role in cancer.'

The preclinical findings were independently validated by multiple research teams, including parallel work led by Professor Ralph DeBerardinis and colleagues at the University of Texas Southwestern Medical Center. The convergence of evidence across independent studies underscores the robustness and integrity of these data, pointing to the status of NUDT5-PPAT as a potential biomarker for personalised therapy and as a target for new treatments in cancer and metabolic disorders.

The work was carried out with collaborators from ETH and the University of Zurich, Switzerland, McGill University, Canada, and supported by the EU Innovative Medicines Initiative programme.

The study  'A non-enzymatic role of Nudix hydrolase 5 in repressing purine de novo synthesis’ is published in Science.

Notes to editors 

For additional images, media enquiries and interview requests contact christopher.mcintyre@admin.ox.ac.uk / press.office@admin.ox.ac.uk.   

The study  A non-enzymatic role of Nudix hydrolase 5 in repressing purine de novo synthesis’ will be published in Science at 19:00 GMT/UTC Thursday 6th November 2025 at 10.1126/science.adv4257. Advance copies of the paper may be obtained from the Science press package, SciPak, at https://www.eurekalert.org/press/scipak/ or by contacting scipak@aaas.org. 

References 

1. Unexpected Noncovalent Off-Target Activity of Clinical BTK Inhibitors Leads to Discovery of a Dual NUDT5/14 Antagonist | Journal of Medicinal Chemistry   

About the University of Oxford 

Oxford University has been placed number 1 in the Times Higher Education World University Rankings for the tenth year running, and ​number 3 in the QS World Rankings 2024. At the heart of this success are the twin-pillars of our ground-breaking research and innovation and our distinctive educational offer. 

Oxford is world-famous for research and teaching excellence and home to some of the most talented people from across the globe. Our work helps the lives of millions, solving real-world problems through a huge network of partnerships and collaborations. The breadth and interdisciplinary nature of our research alongside our personalised approach to teaching sparks imaginative and inventive insights and solutions. 

Through its research commercialisation arm, Oxford University Innovation, Oxford is the highest university patent filer in the UK and is ranked first in the UK for university spinouts, having created more than 300 new companies since 1988. Over a third of these companies have been created in the past five years. The university is a catalyst for prosperity in Oxfordshire and the United Kingdom, contributing around £16.9 billion to the UK economy in 2021/22, and supports more than 90,400 full time jobs. 

About the Nuffield Department of Medicine 

The Centre of Medicines Discovery is a prestigious unit within the Nuffield Department of Medicine (NDM) at the University of Oxford. The NDM is the largest department of medicine in Europe, distinguished by its excellence in several clinical disciplines, including tropical and general medicine, infectious disease, cancer, immunology, gastroenterology, respiratory and renal medicine, and vaccinology. Over the last fifty years, the NDM has pioneered the use of genetics, structural, and cellular biology to understand susceptibility to human disease and prevention of disease in order to improve life for people across the world. NDM has over 1,200 staff in the UK and 2,000 overseas, with over 20 major research institutes, centres and units across Oxford, the UK, Africa and Asia. For more information, visit https://www.ndm.ox.ac.uk/.