Author: Wang, Wenchao ; Liu, Qingsong ; Shi, Chenliang ; Qi, Shuang ; Liang, Qianmao ; Liu, Jing ; Wang, Wenliang ; Wang, Zuowei ; Qi, Ziping ; Wang, Aoli ; Zhou, Bin ; Wang, Junjie ; Wu, Yun ; Wang, Beilei ; Zou, Fengming ; Wang, Li ; Liu, Qingwang

The critical pathogenesis of type 1 diabetes (T1D)/type 2 diabetes (T2D) is the physical status, mass, and function of pancreatic β cells. Mammalian STE20-like protein 1 kinase (MST1) plays vital roles in the apoptosis and insulin secretion of β cells. Here, we discovered a novel, potent, and selective MST1 inhibitor 19 (IC₅₀ = 23 nM), which inhibited the phosphorylation of MST1-protected β cells from the damage of inflammatory cytokines in vitro. In vivo, it displayed acceptable pharmacokinetic properties in different species. In the STZ-induced T1D/T2D mouse models, both monotherapy of 19 and in combination with metformin led to the decline of fasting blood glucose and showed protective effect of β cells. In addition, the combination of 19 and metformin decreased the hemoglobin A1c level. Together, our study suggested that 19 might be a useful pharmacological tool to study MST1-mediated physiology and pathology as well as a potential drug candidate for diabetes.

Signal Transduction and Targeted Therapy

Discovery of IHMT-MST1-39 as a novel MST1 kinase inhibitor and AMPK activator for the treatment of diabetes mellitus

Article

Author: Zou, Fengming ; Shi, Chenliang ; Liu, Qingsong ; Wang, Li ; Wang, Beilei ; Qi, Ziping ; Cao, Jiangyan ; Hu, Chen ; Qi, Shuang ; Liu, Jing ; Wang, Junjie ; Liu, Qingwang ; Liang, Qianmao ; Wang, Wenchao ; Wu, Yun ; Wang, Aoli

AbstractInsulin-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.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus, Type 1	Preclinical	China	Chinese Academy of Sciences	05 Apr 2023
Diabetes Mellitus, Type 2	Preclinical	China	Chinese Academy of Sciences	05 Apr 2023

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