Neratinib protects pancreatic beta cells in diabetes

Abstract

The loss of functional insulin-producing β-cells is a hallmark of diabetes. Mammalian sterile 20-like kinase 1 (MST1) is a key regulator of pancreatic β-cell death and dysfunction; its deficiency restores functional β-cells and normoglycemia. The identification of MST1 inhibitors represents a promising approach for a β-cell-protective diabetes therapy. Here, we identify neratinib, an FDA-approved drug targeting HER2/EGFR dual kinases, as a potent MST1 inhibitor, which improves β-cell survival under multiple diabetogenic conditions in human islets and INS-1E cells. In a pre-clinical study, neratinib attenuates hyperglycemia and improves β-cell function, survival and β-cell mass in type 1 (streptozotocin) and type 2 (obese Leprdb/db) diabetic mouse models. In summary, neratinib is a previously unrecognized inhibitor of MST1 and represents a potential β-cell-protective drug with proof-of-concept in vitro in human islets and in vivo in rodent models of both type 1 and type 2 diabetes.

Treatment with Mammalian Ste-20-like Kinase 1/2 (MST1/2) Inhibitor XMU-MP-1 Improves Glucose Tolerance in Streptozotocin-Induced Diabetes Mice

“…A study using another inhibitor of MST1, Neratinib—which also showed MST1 inhibition to be protective—was also performed using STZ-induced diabetes mellitus [ 17 ]. Our data were consistent with these previous studies.…”

“…MST1 induces β cell death and impairs insulin secretion by initiating proteasomal degradation of pancreatic and duodenal homeobox 1 (PDX1), and β cell transcription factor [ 16 ]. In keeping with this finding, genetic inhibition of MST1 protected against β cell apoptosis and improved the diabetic phenotype in streptozotocin (STZ)-induced diabetes model in mice [ 17 ]. This finding prompted a notion that MST1 could be a novel therapeutic target for DM.…”

“…This finding prompted a notion that MST1 could be a novel therapeutic target for DM. Furthermore, a study using a cancer drug, neratinib, which was found to inhibit MST1 activity, indicated that pharmacological inhibition of MST1 was protective against the development of STZ-induced diabetes mellitus [ 17 ].…”

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–6

“…The discovery of novel agents that may block β-cell apoptosis and at the same time restore β-cell function is of great importance to fight diabetes. Ardestani et al recently demonstrated that neratinib (Figure 7), an FDA-approved drug targeting HER2/EGFR dual kinases, is a potent mammalian sterile 20-like kinase 1 (MST1) inhibitor, which improves β-cell survival under multiple diabetogenic conditions in human islets and INS-1E cells [48]. Five years ago, it was reported that MST1 is a key regulator of pancreatic β-cell death and dysfunction [49].…”

“…20-like kinase 1 (MST1) inhibitor, which improves β-cell survival under multiple diabetogenic conditions in human islets and INS-1E cells [48]. Five years ago, it was reported that MST1 is a key regulator of pancreatic β-cell death and dysfunction [49].…”