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.
Highlights
The loss of functional insulin-producing β-cells is a hallmark of diabetes
As we observed a parallel restoration of β-cell survival and Mammalian sterile 20-like kinase 1 (MST1) inhibition, we aimed to identify whether neratinib can interfere with MST1 downstream signaling and block MST1induced apoptosis
Source data are provided as a Source Data file in glucolipotoxicity-induced apoptosis; these results show that neratinib blocks MST1 signaling and MST1-mediated β-cell apoptosis in islets under diabetogenic conditions
Summary
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. 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. Neratinib forms a covalent interaction with the conserved cysteine residue (Cys-773 in EGFR and Cys-805 in HER2), resulting in tight engagement of the ATP-binding site and robust inhibition of the activation of the EGFR signaling pathway and cell proliferation[34]. This conserved cysteine is not present in MST1. The goal of this work was to evaluate neratinib’s efficacy to prevent apoptosis in human islets and to restore normoglycemia in the streptozotocin (STZ)-induced and in the obese Leprdb/db diabetic mouse models
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