IHMT-MST1-58

IHMT-MST1-58 is a potent, selective mammalian and orally active STE20-like protein 1 kinase (MST1) inhibitor with IC50 value of 23 nM. IHMT-MST1-58 can be used for the research of Type 1/2 diabetes[1].

Signaling Pathways >> Stem Cell/Wnt >> Hippo (MST)

Research Areas >> Metabolic Disease

MST1:23 nM (IC50)

IHMT-MST1-58 (compound 19) shows good activity against MST1 with an IC50 value of 23 nM[1]. IHMT-MST1-58 (1 μM) displays strong inhibitory activity against MST1 (IC50 = 23 nM), weak activity against MST2 (IC50 = 652 nM), but no activity against NEK3 even at 10 μM (IC50 > 10 μM) [1]. IHMT-MST1-58 (1 μM) shows strong binding affinity to MST1 and weak binding affinity to MST2 with Kd values of 240 nM and 2.7 μM[1]. IHMT-MST1-58 (0.1-10 μM; 1-2 h) inhibits the phosphorylation of MST1 in vitro[1]. IHMT-MST1-58 (0.03, 0.1 and 0.3 μM; 48 h) exhibits a significant protective effect of β cells from the damage caused by inflammatory cytokines[1]. Western Blot Analysis[1] Cell Line: HepG2 liver cells, RAW264.7, RPE1 and HL7702 cells; INS-1 and RIN-m5F cell lines Concentration: 0-10 μM Incubation Time: 2 h (HepG2 liver cells, RAW264.7, RPE1, and HL7702 cells) Result: Inhibited the H2O2-stimulated MOB1 phosphorylation and MST1/2 autophosphorylation in a dose-dependent manner in all four cell lines. Inhibited the phosphorylation of LATS1 (T1079) and YAP (S127) in HepG2 cells. Showed strong inhibition of MST1 phosphorylation and its downstream MOB1 autophosphorylation in a dose-dependent manner in both cell lines.

IHMT-MST1-58 (compound 19) (p.o, 50 mg/kg/day, QD) combination with metformin led to the decline of fasting blood glucose, show protective effect of β cells and decrease the hemoglobin A1c level in the STZ-induced T1D/T2D mouse models[1]. Pharmacokinetic Parameters of IHMT-MST1-58 in different species (i.v. or p.o; 1 mg/kg, 5 mg/kg and 10 mg/kg)[1]. mice rats beagle dogs parameter i.v.(1 mg/kg) p.o.(10 mg/kg) i.v.(1 mg/kg) p.o.(10 mg/kg) i.v.(1 mg/kg) p.o.(10 mg/kg) AUC0-t(ng/mL*h) 501.1 5583 2553±155.1 4858±2648 764.5±82.9 4939±1067 t1/2(h) 1.7 1.81 3.51±0.34 3.03±0.2 6.47±0.71 5.79±1.09 Cmax/F (ng/mL) 1240 1922 944.0±219.1 1717±276 466.7±45.2 1113±417 F(%) - 110.8 - 73.3±40.1 - 106.5±20.9 Animal Model: mice[1] Dosage: 50 mg/kg Administration: oral, single Result: parameter plasma pancreas Cmax(ng/mL) 3990±390 12216±1509 AUC0-t(ng/mL*h) 13621±2127 51394±10098 Cl(mL/h/kg) 3734±641 996±189 Animal Model: T1D mouse models and T2D mouse models[1] Dosage: 50 mg/kg Administration: p.o, 50 mg/kg/day, QD Result: Decreased the FBG level, improved the food intake and water consumption, had low HbA1c and a good antidiabetic effect, improved the histological structure of the islet. Animal Model: mice, Sprague Dawley rats, and beagle dogs[1] Dosage: 1 mg/kg, 5 mg/kg and 10 mg/kg Administration: intravenous injection and oral administration Result: Displayed acceptable pharmacokinetic properties in different species.

[1]. Yun Wu, et al. Discovery of IHMT-MST1-58 as a Novel, Potent, and Selective MST1 Inhibitor for the Treatment of Type 1/2 Diabetes. J Med Chem. 2022 Sep 8;65(17):11818-11839