 |
| Experimental Drug RAGE406R Offers New Hope in Treating Diabetes-Related Organ Damage |
BLOGSIA.EU.ORG - A breakthrough in diabetes research has emerged from scientists at NYU Langone Health, who have developed a new experimental drug called RAGE406R.
This small-molecule compound has shown significant promise in reducing inflammation, cell damage, and organ injury commonly associated with both Type 1 and Type 2 diabetes. Unlike existing therapies that mainly focus on lowering blood sugar, RAGE406R works by targeting the underlying molecular pathways that drive diabetic complications.
In the study, which appeared as a cover story in Cell Chemical Biology, researchers discovered that RAGE406R disrupts the interaction between two key proteins, RAGE and DIAPH1.
In the study, which appeared as a cover story in Cell Chemical Biology, researchers discovered that RAGE406R disrupts the interaction between two key proteins, RAGE and DIAPH1.
This protein pair has long been linked to diabetes-related damage in the heart, kidneys, and other organs, as well as delayed wound healing. By blocking DIAPH1 from binding to RAGE, RAGE406R was able to reduce inflammation and accelerate tissue recovery in both human cells and diabetic mice.
“There are currently no treatments that address the root causes of diabetic complications, and our work shows that RAGE406R can – not by lowering the high blood sugar, but instead by blocking the intracellular action of RAGE,” said co-senior study author Ann Marie Schmidt, MD, the Dr. Iven Young Professor of Endocrinology at the NYU Grossman School of Medicine. “If confirmed by further testing in human trials, the compound could potentially fill gaps in treatment, including that most current drugs work only against Type 2 diabetes.”
The RAGE protein, short for “receptor for advanced glycation end products,” interacts with signaling molecules that form when fats or proteins combine with sugars — a process that occurs more frequently in people with diabetes. These molecules, known as AGEs, tend to build up in the blood over time, contributing to inflammation and tissue damage. The study found that RAGE406R competes with DIAPH1 for a binding site on RAGE, preventing the harmful complex from forming inside cells. This mechanism interrupts the formation of actin filaments, structural elements that, when overproduced, worsen diabetic complications.
Schmidt’s team previously screened more than 58,000 molecules to identify compounds that could safely block this RAGE-DIAPH1 interaction. An earlier drug candidate, RAGE229, showed promise but was later found to contain a chemical structure that could potentially alter DNA and increase cancer risk. RAGE406R was redesigned to eliminate this concern while maintaining its therapeutic effectiveness.
When tested in obese mice with Type 2 diabetes, RAGE406R was applied topically to wounds and successfully accelerated wound closure in both male and female mice. The compound’s effectiveness appears to stem from its influence on the body’s immune response. In diabetes, the immune system often misfires, causing inflammation in healthy tissues. RAGE406R reduced levels of a proinflammatory chemical called CCL2, calming immune cells known as macrophages and promoting tissue repair.
“Our findings point to a promising new pathway for treating diabetes in the future,” said co-senior study author Alexander Shekhtman, PhD, a professor in the Department of Chemistry at the State University of New York (SUNY) at Albany. “The current study results serve as a springboard for the development of therapies for both types of diabetes, and for designing markers that can measure how well the new treatment works in live animals.”
The research, titled “RAGE-mediated activation of the formin DIAPH1 and human macrophage inflammation are inhibited by a small molecule antagonist,” was published on October 1, 2025, in Cell Chemical Biology (DOI: 10.1016/j.chembiol.2025.09.004). The work was supported by grants from the U.S. Public Health Service and the NYU Grossman School of Medicine’s Diabetes Research Program.
The discovery of RAGE406R marks a significant step toward a new era of diabetes treatment. By directly addressing the molecular causes of inflammation and tissue injury, the compound could fill a long-standing void in diabetes care. If future human trials confirm these findings, RAGE406R may become the first therapy to prevent diabetic complications at their source, potentially transforming outcomes for millions of patients worldwide.
“There are currently no treatments that address the root causes of diabetic complications, and our work shows that RAGE406R can – not by lowering the high blood sugar, but instead by blocking the intracellular action of RAGE,” said co-senior study author Ann Marie Schmidt, MD, the Dr. Iven Young Professor of Endocrinology at the NYU Grossman School of Medicine. “If confirmed by further testing in human trials, the compound could potentially fill gaps in treatment, including that most current drugs work only against Type 2 diabetes.”
The RAGE protein, short for “receptor for advanced glycation end products,” interacts with signaling molecules that form when fats or proteins combine with sugars — a process that occurs more frequently in people with diabetes. These molecules, known as AGEs, tend to build up in the blood over time, contributing to inflammation and tissue damage. The study found that RAGE406R competes with DIAPH1 for a binding site on RAGE, preventing the harmful complex from forming inside cells. This mechanism interrupts the formation of actin filaments, structural elements that, when overproduced, worsen diabetic complications.
Schmidt’s team previously screened more than 58,000 molecules to identify compounds that could safely block this RAGE-DIAPH1 interaction. An earlier drug candidate, RAGE229, showed promise but was later found to contain a chemical structure that could potentially alter DNA and increase cancer risk. RAGE406R was redesigned to eliminate this concern while maintaining its therapeutic effectiveness.
When tested in obese mice with Type 2 diabetes, RAGE406R was applied topically to wounds and successfully accelerated wound closure in both male and female mice. The compound’s effectiveness appears to stem from its influence on the body’s immune response. In diabetes, the immune system often misfires, causing inflammation in healthy tissues. RAGE406R reduced levels of a proinflammatory chemical called CCL2, calming immune cells known as macrophages and promoting tissue repair.
“Our findings point to a promising new pathway for treating diabetes in the future,” said co-senior study author Alexander Shekhtman, PhD, a professor in the Department of Chemistry at the State University of New York (SUNY) at Albany. “The current study results serve as a springboard for the development of therapies for both types of diabetes, and for designing markers that can measure how well the new treatment works in live animals.”
The research, titled “RAGE-mediated activation of the formin DIAPH1 and human macrophage inflammation are inhibited by a small molecule antagonist,” was published on October 1, 2025, in Cell Chemical Biology (DOI: 10.1016/j.chembiol.2025.09.004). The work was supported by grants from the U.S. Public Health Service and the NYU Grossman School of Medicine’s Diabetes Research Program.
The discovery of RAGE406R marks a significant step toward a new era of diabetes treatment. By directly addressing the molecular causes of inflammation and tissue injury, the compound could fill a long-standing void in diabetes care. If future human trials confirm these findings, RAGE406R may become the first therapy to prevent diabetic complications at their source, potentially transforming outcomes for millions of patients worldwide.
(*)
Source: 1
