Discovery of IHMT-MST1-58 as a Novel, Potent, and Selective MST1 Inhibitor for the Treatment of Type 1/2 Diabetes

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.