For more than seven decades, doctors have used the drug 6-thioguanine (6-TG) to treat leukemia. Its effects in patients are well documented, but researchers are still working to understand the molecular details that determine why some cells are killed by the drug while others manage to withstand it. A team at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, working with scientists at the University of Oxford, the Weizmann Institute of Science and the University of Dundee, has now identified an unexpected factor in that response: a protein called NUDT5.
The finding follows a recent discovery from the Kubicek and Huber laboratories (Science, 2025). That earlier work showed that NUDT5 has an important role inside cells that does not depend on its usual enzymatic activity. Rather than functioning only as a catalyst that drives chemical reactions, NUDT5 can also act as a molecular scaffold that helps organize cellular metabolism.
That unusual function appears to matter for how cells respond to 6-TG. "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." Removing NUDT5 Changes the Drug Response Many drugs that target enzymes are designed to block the chemical reactions those enzymes perform. The researchers wanted to know whether suppressing NUDT5 in this way would also change the effects of 6-TG. To test that idea, they used an emerging strategy known as targeted protein degradation.
Instead of merely blocking a protein's activity, this method causes the cell to eliminate the protein altogether. "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," said Anne-Sophie Marques, a first author of the paper whose work at Oxford contributed to the findings.
A medicinal chemistry program led by the Huber laboratory at the University of Oxford produced a collection of highly selective NUDT5 degraders. The researchers also created matched control compounds that could bind to NUDT5 without causing the protein to be destroyed. They then compared the effects of these molecules with conventional NUDT5 inhibitors.
Extract — continue reading at the source.
