MADISON, Wis. — A study published in Nature Communications reports new findings on how cancer cells respond to targeted drugs, identifying a direct connection between tumor metabolic conditions and drug engagement inside live cells. The work is the result of a collaboration among Promega, the Center for Advanced Study of Drug Action at the State University of New York at Stony Brook, and the Centre for Medicines Discovery at the University of Oxford, with additional contributions from Boston University and the Structural Genomics Consortium at the University of Toronto.
The research used Promega’s bioluminescent NanoBRET Target Engagement technology to study inhibitors that exploit synthetic lethality pathways. The results show how the metabolic state of cancer cells influences the effectiveness of drugs aimed at PRMT5, a protein long viewed as a promising target in oncology.
“The methods in this study enable us to characterize inhibitors that bind much more tightly in tumor cells with specific mutations,” said Ani Michaud, Sr Research Scientist at Promega and co-first author of the paper. “To our knowledge, this is the first time anyone has characterized this type of uncompetitive inhibitor mechanism directly in live cells.”
The study centers on cancers with deletions in the MTAP gene, which occur in roughly 10 to 15 percent of tumors. In normal cells, PRMT5 interacts with a molecule known as SAM. In MTAP-deleted tumor cells, that interaction shifts to a different molecule, MTA, reducing PRMT5 activity and creating a selective vulnerability that drug developers have sought to target.
Researchers at Oxford designed a new BRET probe, CBH-002, to monitor drug engagement with PRMT5 inside live cells. Dr Elisabeth Mira Rothweiler, Postdoctoral Researcher at the Centre for Medicines Discovery and co-first author, said the probe revealed how metabolic conditions shape drug behavior. “CBH-002 could measure various PRMT5 inhibitor types in live cells, prompting us to test its sensitivity to the cofactor SAM. When we discovered the probe’s ability to sense metabolite levels, it established its utility as a metabolic biosensor. Through collaboration with Promega, we demonstrated how MTA influences drug selectivity, revealing why certain inhibitors are so effective in MTAP-deleted cancers.”
Her work supports approaches that design drugs to take advantage of metabolic differences between cancerous and healthy tissue, potentially improving selectivity and reducing side effects.
The study also marks the first time uncompetitive, or cooperative, binding of PRMT5 inhibitors has been demonstrated directly in living cells. Biochemical experiments have hinted at such mechanisms, but they have not always matched cell-based results. The NanoBRET assay used in this work allowed researchers to see binding behavior in a cellular environment where metabolic factors are active.
Professor Kilian Huber, Associate Professor at the Centre for Medicines Discovery and co-senior author, said the findings offer clearer insight into why some PRMT5 inhibitors show strong activity only in MTAP-deleted tumors. “The biosensor lets us examine, in living cells, how different PRMT5 inhibitors behave under the specific metabolic conditions that make some tumors uniquely vulnerable. This provides unprecedented insight into why certain inhibitors are much more effective in cancers lacking MTAP and paves the way for highly targeted cancer treatment in the future. It’s like turning on the lights inside the cell so we can finally see which key actually fits the lock.”
Peter Tonge, distinguished professor of chemistry and director of the Center for Advanced Study of Drug Action at the State University of New York at Stony Brook, said the findings support efforts to build tumor-selective therapies. “Selectivity is one of the most critical challenges in cancer therapy, as most treatments also damage healthy cells, leading to dose-limiting toxicities and reduced therapeutic effectiveness,” he said. “A new class of tumor-specific drugs addresses this by acting uncompetitively with a metabolite that accumulates only in cancer cells, limiting activity to tumor tissue. We have now developed the first technology to quantify the activity of these drugs directly in live cells, providing a foundation for optimizing and advancing next-generation precision oncology therapeutics.”
Matt Robers, Associate Director of R&D at Promega and co-senior author, said the study highlights what academic–industry collaborations can produce. “This work underscores the value of research collaborations between academia and industry,” he said. “By combining our complementary expertise in chemical biology and assay design, we were able to dissect how cooperativity can drive cancer cell selectivity. These findings have real potential to guide the development of future precision medicines.”
