Senior author of the study and Chief Operating Officer of Calibr and Scripps Research, Matthew Tremblay, PhD, and colleagues at University of Bremen in Germany explored opportunities to preserve and regain the insulin-producing function of beta cells in diabetic patients. In their prior studies on diabetic mice, the team had found that the enzyme mammalian sterile 20-like kinase 1 (MST1) was instrumental in the activation of cell signals that trigger beta-cell dysfunction and death. Prior to the team’s work on mice, the protective effect of MST1 signaling inhibition was not recognized.
The researchers recognized that if the cell signals responsible for the damage to, or the death of, beta cells could be eliminated or blocked, the result might be the protection of beta cells and the prevention of diabetes. The team decided to investigate existing FDA-approved drugs that could accomplish this same protective mechanism of action and that might be able to be repurposed in improving the function of beta cells and blood-glucose regulation. The researchers found it to be a key pharmacologic contributor to the restoration of beta-cell function and survival.
In the current study, the researchers screened 641 drug-like kinase inhibitors and determined that neratinib, which is FDA approved for breast cancer treatment, was a potent MST1 inhibitor. Using human islets and type 1 and type 2 diabetic mice, the team studied neratinib’s protective impact on beta-cell function, survival, and reduced instances of hyperglycemia. After treating diabetic mice for a month with neratinib, the team discovered significantly restored beta-cell survival and function. Other notable improvements were reported in reduction and prevention of elevated blood glucose over time. The team reported a “robust pro-survival effect was also observed in human islets, which are areas of the pancreas that contain beta cells.”
The authors concluded that this previously unappreciated inhibitor of MST1 now represents a novel potential beta cell–protective medication in vitro in human islets and in vivo in rodent models of both type 1 and type 2 diabetes. According to the authors, “Repurposing of FDA-approved drugs has been a topic of great interest amidst the escalating costs of new drug development, particularly in the case of diseases with high-unmet medical need such as type 1 diabetes.” The authors went on to say, “The discovery of neratinib’s ability to protect beta cells amounts to an accelerated path to a preclinical proof of concept,” and concluded that it represents “a firm basis for follow-up work on next-generation compounds that could add to the treatment options for diabetes.”
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