Discovery of IHMT-MST1-39 as a novel MST1 kinase inhibitor and AMPK activator for the treatment of diabetes mellitus.
Signal Transduct Target Ther
; 8(1): 143, 2023 04 05.
Article
en En
| MEDLINE
| ID: mdl-37015918
ABSTRACT
Insulin-producing pancreatic ß cell death is the fundamental cause of type 1 diabetes (T1D) and a contributing factor to type 2 diabetes (T2D). Moreover, metabolic disorder is another hallmark of T2D. Mammalian sterile 20-like kinase 1 (MST1) contributes to the progression of diabetes mellitus through apoptosis induction and acceleration of pancreatic ß cell dysfunction. AMP-activated protein kinase (AMPK) is an energy sensing kinase and its activation has been suggested as a treatment option for metabolic diseases. Thus, pharmacological inhibition of MST1 and activation of AMPK simultaneously represents a promising approach for diabetes therapy. Here, we discovered a novel selective MST1 kinase inhibitor IHMT-MST1-39, which exhibits anti-apoptosis efficacy and improves the survival of pancreatic ß cells under diabetogenic conditions, as well as primary pancreatic islets in an ex vivo disease model. Mechanistically, IHMT-MST1-39 activated AMPK signaling pathway in hepatocytes in vitro, combination of IHMT-MST1-39 and metformin synergistically prevented hyperglycemia and significantly ameliorated glucose tolerance and insulin resistance in diabetic mice. Taken together, IHMT-MST1-39 is a promising anti-diabetic candidate as a single agent or in combination therapy for both T1D and T2D.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Diabetes Mellitus Experimental
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Diabetes Mellitus Tipo 1
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Diabetes Mellitus Tipo 2
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Signal Transduct Target Ther
Año:
2023
Tipo del documento:
Article