Neratinib protects pancreatic beta cells in diabetes

Amin Ardestani (), Sijia Li, Karthika Annamalai, Blaz Lupse, Shirin Geravandi, Aleksandra Dobrowolski, Shan Yu, Siying Zhu, Tyler D. Baguley, Murali Surakattula, Janina Oetjen, Lena Hauberg-Lotte, Raquel Herranz, Sushil Awal, Delsi Altenhofen, Nguyen-Tran Van, Sean Joseph, Peter G. Schultz, Arnab K. Chatterjee, Nikki Rogers, Matthew S. Tremblay (), Weijun Shen () and Kathrin Maedler ()
Additional contact information
Amin Ardestani: University of Bremen
Sijia Li: Calibr at Scripps Research
Karthika Annamalai: University of Bremen
Blaz Lupse: University of Bremen
Shirin Geravandi: University of Bremen
Aleksandra Dobrowolski: University of Bremen
Shan Yu: Calibr at Scripps Research
Siying Zhu: Calibr at Scripps Research
Tyler D. Baguley: Calibr at Scripps Research
Murali Surakattula: Calibr at Scripps Research
Janina Oetjen: University of Bremen
Lena Hauberg-Lotte: University of Bremen
Raquel Herranz: University of Bremen
Sushil Awal: University of Bremen
Delsi Altenhofen: University of Bremen
Nguyen-Tran Van: Calibr at Scripps Research
Sean Joseph: Calibr at Scripps Research
Peter G. Schultz: Calibr at Scripps Research
Arnab K. Chatterjee: Calibr at Scripps Research
Nikki Rogers: Calibr at Scripps Research
Matthew S. Tremblay: Calibr at Scripps Research
Weijun Shen: Calibr at Scripps Research
Kathrin Maedler: University of Bremen

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12880-5

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