Study Establishes Molecular Link Between Tumor Metabolism and Drug Engagement in Cancer Cells

• Researchers studied synthetic lethality pathway using Promega NanoBRET^® TE technology
• Study is the first to characterize uncompetitive binding directly in live cells, illuminating a mechanistic bridge between cancer metabolism and precision oncology
• Published paper is the product of collaboration between Promega, University of Oxford's Centre for Medicines Discovery and Stony Brook University's Center for Advanced Discovery of Drug Action

Madison, WI USA. (December 9, 2025)

A new study published in Nature Communications reveals technological advances that accelerate breakthroughs in precision medicine. Conducted as a collaboration between 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, the work leverages bioluminescent NanoBRET^® Target Engagement (TE) technology developed by Promega to characterize inhibitors that selectively target cancer cells without harming noncancerous cells. Their results demonstrate a connection between drug efficacy and tumor metabolic state, offering a mechanistic bridge between cancer metabolism and precision oncology.

"The methods in this study enable us to characterize inhibitors that bind much more tightly in tumor cells with specific mutations," says Ani Michaud, Sr Research Scientist at Promega and co-first author of the Nature Communications paper. "To our knowledge, this is the first time anyone has characterized this type of uncompetitive inhibitor mechanism directly in live cells."

PRMT5: Top Target for Drug Discovery

The published study focuses on a gene-regulating protein called PRMT5, which has long been considered a top target for drug discovery. In normal cells, PRMT5 interacts with a molecule called SAM. However, in the tumor cells of approximately 10-15% of cancers, a deletion of the MTAP gene leads to PRMT5 interacting with the molecule MTA instead, reducing its function. This difference creates a key vulnerability for targeting cancer cells with a mutation to MTAP while leaving normal cells unaffected.

The University of Oxford team designed and developed CBH-002, a cell-permeable BRET probe that binds to a genetically encoded PRMT5-NanoLuc biosensor to report drug target engagement in live cells.

Dr Elisabeth Mira Rothweiler, Postdoctoral Researcher, Centre for Medicines Discovery, University of Oxford and co-first author, says: "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."

Dr Rothweiler's research further enables a strategy for developing molecules that exploit the metabolic vulnerabilities specific to MTAP-deleted cancers, potentially offering highly targeted treatments with minimal effects on healthy tissue.

Uncompetitive Binding in Live Cells

While past studies have characterized this mechanism-of-action (MoA) in biochemical assays, this is the first to use NanoBRET TE technology to characterize uncompetitive, or cooperative, binding in live cells. Biochemical assays can reveal uncompetitive MoAs, but there is often a discrepancy between biochemical data and functional assays like selective cell killing. The NanoBRET TE assay used in this study bridges the two modalities, showing binding MoA in a cellular context that aligns with functional assay results.

Professor Kilian Huber, Associate Professor, Centre for Medicines Discovery, University of Oxford and co-senior author of the study, says, "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."

"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," says 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 and visiting professor at the University of Rochester. "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."

Collaboration Between Academia and Industry

This study was the result of collaboration between 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 researchers at Boston University and the Structural Genomics Consortium at the University of Toronto.

"This work underscores the value of research collaborations between academia and industry," says Matt Robers, Associate Director of R&D at Promega and co-senior author of the study. "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."

Promega Corporation is a leader in providing innovative solutions and technical support to the life sciences industry. The company's portfolio of over 4,000 products supports a range of life science work across areas such as cell biology; DNA, RNA and protein analysis; drug development; human identification and molecular diagnostics. These tools and technologies have grown in their application over the last 45 years and are used today by scientists and technicians in labs for academic and government research, forensics, pharmaceuticals, clinical diagnostics and agricultural and environmental testing. Promega is headquartered in Madison, WI, USA with branches in 16 countries and over 50 global distributors.

The Centre for 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. It is distinguished by its excellence in several clinical disciplines, including cancer, tropical and general medicine, infectious disease, 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, while maintaining a focus on clinical medicine. NDM has over 1,200 staff in the UK and 2,000 overseas, with over 20 major research institutes, centres and units in Oxford as well as Kenya, Thailand, Vietnam and Indonesia. For more information, visit https://www.ndm.ox.ac.uk/

The State University of New York at Stony Brook is New York's flagship university and No. 1 public university. It is part of the State University of New York (SUNY) system. With more than 26,000 students, more than 3,000 faculty members, more than 225,000 alumni, a premier academic healthcare system and 18 NCAA Division I athletic programs, Stony Brook is a research-intensive distinguished center of innovation dedicated to addressing the world's biggest challenges. The university embraces its mission to provide comprehensive undergraduate, graduate and professional education of the highest quality, and is ranked as the #58 overall university and #26 among public universities in the nation by U.S. News & World Report's Best Colleges listing. Fostering a commitment to academic research and intellectual endeavors, Stony Brook's membership in the Association of American Universities (AAU) places it among the top 71 research institutions in North America. The university's distinguished faculty have earned esteemed awards such as the Nobel Prize, Pulitzer Prize, Indianapolis Prize for animal conservation, Abel Prize, Fields Medal and Breakthrough Prizes in Mathematics and Physics. Stony Brook has the responsibility of co-managing Brookhaven National Laboratory for the U.S. Department of Energy - one of only eight universities with a role in running a national laboratory. In 2023, Stony Brook was named the anchor institution for The New York Climate Exchange on Governors Island in New York City. Providing economic growth for neighboring communities and the wider geographic region, the university totals an impressive $8.93 billion in increased economic output on Long Island. Follow us on Facebook https://www.facebook.com/stonybrooku/ and X@stonybrooku.

Read the paper in Nature Communciations