Discovery of IHMT-MST1-39 as a novel MST1 kinase inhibitor and AMPK activator for the treatment of diabetes mellitus.
Junjie WangZiping QiYun WuAoli WangQingwang LiuFengming ZouBeilei WangShuang QiJiangyan CaoChen HuChenliang ShiQianmao LiangLi WangJing LiuWenchao WangQing-Song LiuPublished in: Signal transduction and targeted therapy (2023)
Insulin-producing pancreatic β 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 β 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 β 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.
Keyphrases
- protein kinase
- type diabetes
- cell death
- cell cycle arrest
- glycemic control
- oxidative stress
- skeletal muscle
- signaling pathway
- pi k akt
- induced apoptosis
- endoplasmic reticulum stress
- cardiovascular disease
- small molecule
- stem cells
- metabolic syndrome
- insulin resistance
- cell therapy
- cell proliferation
- adipose tissue
- epithelial mesenchymal transition
- toll like receptor