A new study published in Nature Communications highlights a breakthrough in precision medicine by uncovering how tumor metabolism influences drug engagement in cancer cells. The research was conducted through 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 team utilized Promega’s bioluminescent NanoBRET Target Engagement technology to study inhibitors that selectively target cancer cells while sparing healthy cells. Their findings reveal a direct link between the metabolic state of tumors and drug effectiveness, providing a molecular explanation for selective cancer therapies.
Health Technology Insights: Innovent Biologics Forms Global Partnership with Takeda
“To our knowledge, this is the first time anyone has characterized this type of uncompetitive inhibitor mechanism directly in live cells,” said Ani Michaud, Senior Research Scientist at Promega. Michaud, a co-first author of the study, added that the approach enables precise measurement of inhibitors that bind more tightly in tumor cells with specific mutations, bridging the gap between functional assays and biochemical data.
The study focuses on PRMT5, a gene-regulating protein considered a top target for drug discovery. In normal cells, PRMT5 interacts with SAM, but in approximately 10 to 15 percent of cancers where the MTAP gene is deleted, PRMT5 binds with MTA instead, reducing its activity. This metabolic difference creates a vulnerability that allows drugs to selectively target tumor cells. The University of Oxford team developed CBH-002, a BRET probe that works with a PRMT5-NanoLuc biosensor to measure drug engagement in live cells.
Health Technology Insights: Catalight Chief Clinical Officer Dr. Doreen Samelson Wins 2025 Merit Award
Dr Elisabeth Mira Rothweiler, Postdoctoral Researcher at the University of Oxford and co-first author, explained that CBH-002 can sense metabolite levels and measure the impact of SAM on PRMT5 inhibitors. She noted that this capability revealed why certain inhibitors are highly effective in MTAP-deleted cancers and supports the design of therapies that exploit these metabolic vulnerabilities to minimize harm to healthy tissue.
This research is the first to apply NanoBRET TE technology to observe uncompetitive, or cooperative, binding mechanisms in living cells. Prior studies could measure this only in biochemical assays, which often fail to reflect functional outcomes. The NanoBRET TE method aligns biochemical data with real cellular responses, demonstrating how specific inhibitors operate in tumor environments.
Professor Kilian Huber, Associate Professor at the University of Oxford and co-senior author, emphasized that the biosensor allows researchers to see how PRMT5 inhibitors perform under the metabolic conditions unique to certain tumors, providing critical insights for precision oncology. Peter Tonge, Distinguished Professor of Chemistry at SUNY Stony Brook, highlighted that tumor-selective drugs reduce off-target effects on healthy cells, addressing one of the most significant challenges in cancer therapy.
Matt Robers, Associate Director of R&D at Promega and co-senior author, underscored the importance of collaboration between academia and industry in this project. He noted that combining expertise in assay design and chemical biology enabled the team to uncover the cooperative mechanisms driving cancer cell selectivity. The findings provide a foundation for developing next-generation therapies that are highly targeted and efficient.
This study represents a key advance in the understanding of tumor-specific drug engagement and demonstrates the potential of integrating live-cell assay technologies with precision medicine strategies to improve outcomes for patients with cancer.
Health Technology Insights: Avantor Appoints Sanjeev Mehra to its Board of Directors
To participate in our interviews, please write to our HealthTech Media Room at info@intentamplify.com
