University of Minnesota Advances Precision Medicines with New Molecules

New research from the University of Minnesota Medical School reveals promising developments in the field of precision medicine. Scientists have discovered that molecules functioning as “molecular bumpers” and “molecular glues” can effectively alter G protein-coupled receptor (GPCR) signaling. This breakthrough opens pathways for a new class of safer and more targeted medications. The findings were published in the prestigious journal Nature on March 15, 2025.

GPCRs represent a significant area in pharmacology, as nearly one-third of drugs approved by the Food and Drug Administration target this family of receptors. Despite their success, researchers believe there remains substantial untapped potential for developing new treatments targeting these receptors. GPCRs can activate various signaling pathways linked to 16 different G proteins, leading to diverse cellular and physiological effects. While some of these pathways can be therapeutically beneficial, others may cause adverse side effects, posing challenges for drug development.

Dr. Lauren Slosky, an assistant professor at the University of Minnesota Medical School and the senior author of the study, emphasized the potential of designing drugs that selectively produce desired signaling outcomes. “The capability to design drugs that produce only selected signaling outcomes may yield safer, more effective medicines. Until now, it hasn’t been obvious how to do this,” she stated.

The research team, which included chemists from the Sanford Burnham Prebys Medical Discovery Institute (SBP), outlined a method for creating compounds that activate specific normal signaling pathways of GPCRs. Unlike most existing GPCR-targeting drugs that interact with receptors from outside the cell, these new compounds bind to a previously unexploited site within the cell. This allows them to engage directly with signaling partners.

In their examination of the neurotensin receptor 1, a specific type of GPCR, the researchers found that these compounds can serve dual functions. They act as molecular glues—facilitating interactions with certain signaling partners—and as molecular bumpers—blocking interactions with others. Dr. Slosky noted, “Most drugs ‘turn up’ or ‘turn down’ all of a receptor’s signaling uniformly. In addition to ‘volume control,’ these new compounds change the message received by the cell.”

Through computational modeling, the team successfully designed compounds that exhibit varied signaling profiles, resulting in distinct biological outcomes. Dr. Steven Olson, executive director of Medicinal Chemistry at SBP and a co-author of the study, explained, “We controlled which signaling pathways were turned on and which ones were turned off by changing the chemical structure of the compound. Most importantly, these changes were predictable and can be used by medicinal chemists to rationally design new drugs.”

The ultimate aim for these compounds targeting the neurotensin receptor 1 is to develop treatments for chronic pain and addiction while minimizing side effects. Given that this intracellular binding site is common among the GPCR superfamily, the implications of this strategy extend to various receptors, potentially leading to innovative therapies for a wide range of diseases.

The study represents a significant step forward in the quest for precision medicine, offering the possibility of more effective treatments with fewer adverse effects. As researchers continue to explore the potential of molecular glues and bumpers, the landscape of therapeutic development may be on the brink of transformation.