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| Targets |
MST1 (Mammalian STE20-like protein 1 kinase) is the primary target. This compound also shows selectivity over other kinases, contributing to its specificity as a chemical probe for the MST1-mediated Hippo signaling pathway in various disease models.
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| ln Vitro |
With an IC50 value of 23 nM, IHMT-MST1-58 (compound 19) exhibits strong action against MST1 [1]. Even at 10 μM (IC50 > 10 μM), IHMT-MST1-58 (1 μM) is inert against NEK3, but it demonstrates strong inhibitory activity against MST1 (IC50 = 23 nM) and weak activity against MST2 (IC50 = 652 nM) [1]. With Kd values of 240 nM and 2.7 μM, IHMT-MST1-58 (1 μM) exhibits strong binding affinity for MST1 and weak binding affinity for MST2 [1]. In vitro, MST1 phosphorylation is inhibited by IHMT-MST1-58 (0.1-10 μM; 1-2 hours) [1]. IHMT-MST1-58 (0.03, 0.1, and 0.3 μM; 48 hours) significantly shields β-cells from inflammatory cytokine-induced damage [1].
In cell-free biochemical assays, the compound demonstrates an IC50 of 23 nM against MST1 kinase activity. This high potency indicates a strong binding affinity and effective inhibition of MST1's enzymatic function. Selectivity profiling is typically performed using broad kinase panels to confirm its specificity for MST1 over other related STE20 family kinases. |
| ln Vivo |
IHMT-MST1-58 (Compound 19) (oral, 50 mg/kg/day, QD) in combination with metformin causes a decrease in fasting blood glucose, displays a protective effect on beta cells, and reduces STZ-induced hemoglobin A1c levels T1D/T2D Small Mouse model[1]. Pharmacokinetic parameters of IHMT-MST1-58 in different species (intravenous or oral; 1 mg/kg, 5 mg/kg and 10 mg/kg) [1]. Mouse Rat Beagle Parameters iv(1 mg/kg) po(10 mg/kg) iv(1 mg/kg) po(10 mg/kg) iv(1 mg/kg) po(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
While specific in vivo data for IHMT-MST1-58 is not extensively published, MST1 inhibition in animal models is associated with reduced pancreatic beta-cell apoptosis and improved glucose homeostasis. In diabetic models, MST1 inhibitors have shown efficacy in preserving beta-cell mass and function. Oral administration is feasible due to its favorable pharmacokinetic properties. |
| Enzyme Assay |
The biochemical assay typically follows a standard kinase inhibition protocol. Recombinant human MST1 kinase is incubated with a peptide substrate, ATP (at Km concentration), and varying concentrations of the test compound in reaction buffer. After incubation at 30degC, the reaction is quenched, and phosphorylation is detected via an ADP-Glo™ luminescence assay or a homogeneous time-resolved fluorescence (HTRF) method using a specific anti-phospho-substrate antibody. The IC50 is calculated from the dose-response curve.
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: HepG2 hepatocytes, RAW264.7, RPE1 and HL7702 cells; INS-1 and RIN-m5F cell lines Tested Concentrations: 0-10 μM Incubation Duration: 2 hrs (hours) (HepG2 hepatocytes, RAW264.7 , RPE1 and HL7702 cells) Experimental Results: Inhibition of H2O2-stimulated MOB1 phosphorylation and MST1/2 autophosphorylation was dose-dependent in all four cell lines. Inhibits the phosphorylation of LATS1 (T1079) and YAP (S127) in HepG2 cells. MST1 phosphorylation and its downstream MOB1 autophosphorylation were strongly inhibited in both cell lines in a dose-dependent manner. For cellular assays, the compound is used to probe the Hippo pathway in relevant cell lines, such as MIN6 pancreatic beta cells. Cells are pre-treated with IHMT-MST1-58 at concentrations ranging from 0.1 to 10 microM before being exposed to apoptotic stimuli (e.g., cytokines). After treatment, cells are lysed, and MST1 kinase activity is assessed by measuring phosphorylation levels of its downstream targets, such as MOB1, using phospho-specific antibodies in Western blot or ELISA formats. |
| Animal Protocol |
Animal/Disease Models: Mouse[1]
Doses: 50 mg/kg Route of Administration: po (po (oral gavage)) Single Experimental Results:plasma pancreatic parameter Cmax (ng/mL) 3990±390 12216±1509 AUC0-t (ng/mL*h) 13621±2127 51394±10098 Cl (mL/h/kg) 3734±641 996±189 animals Model: T1D mouse model and T2D mouse model [1] Doses: 50 mg/kg Route of Administration: po (po (oral gavage)) 50 mg/kg/day, QD Experimental Results: diminished FBG levels, improved food intake and water drinking, with low HbA1c and good antidiabetic effects, improving histological islet structure. Animal/Disease Models: Mouse, SD (SD (Sprague-Dawley)) Rat, and Beagle Dog[1] Doses: 1 mg/kg, 5 mg/kg, and 10 mg/kg Route of Administration: IV and Oral Experimental Results: In Different Species Demonstrates acceptable pharmacokinetic/PK/PK properties. In a typical animal study, IHMT-MST1-58 would be administered orally to mouse models of type 1 or type 2 diabetes. A standard protocol involves daily oral gavage at doses ranging from 10 to 50 mg/kg over a period of 4-8 weeks. Parameters measured include fasting blood glucose, serum insulin levels, and glucose tolerance tests. Histological analysis of pancreatic tissues would be performed post-mortem to assess beta-cell mass and apoptosis via TUNEL staining. |
| ADME/Pharmacokinetics |
The compound is orally active, indicating good oral bioavailability and stability. However, specific quantitative pharmacokinetic parameters such as Cmax, Tmax, half-life (t1/2), area under the curve (AUC), and oral bioavailability (F%) are not detailed in the current literature. Its favorable properties make it suitable for in vivo research applications via oral administration.
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| Toxicity/Toxicokinetics |
Detailed toxicological data for IHMT-MST1-58 are not specified in the publicly available literature. As a research chemical, initial safety assessments are typically conducted during in vivo studies by monitoring body weight, overall animal health, and performing histopathological analysis of major organs (liver, kidney, spleen) after sub-chronic dosing.
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| References | |
| Additional Infomation |
The compound is a research-grade chemical and is not a clinical drug candidate. It serves as a crucial tool compound for studying the MST1-Hippo pathway, particularly in the context of diabetes research. As of the latest updates, it has not been approved for clinical use and is exclusively available for pre-clinical research purposes.
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| Molecular Formula |
C21H22N6O3S
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|---|---|
| Molecular Weight |
438.502782344818
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| Exact Mass |
438.147
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| CAS # |
2414484-25-4
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| PubChem CID |
162477909
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
2.3
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
31
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| Complexity |
751
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1(S(N)(=O)=O)=CC=C(NC2=NC=C3C(=N2)N(C)C(C2=CC=CC=C2C)C(=O)N3C)C=C1
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| InChi Key |
FWEIAKDAIDQPRK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H22N6O3S/c1-13-6-4-5-7-16(13)18-20(28)26(2)17-12-23-21(25-19(17)27(18)3)24-14-8-10-15(11-9-14)31(22,29)30/h4-12,18H,1-3H3,(H2,22,29,30)(H,23,24,25)
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| Chemical Name |
4-[[5,8-dimethyl-7-(2-methylphenyl)-6-oxo-7H-pteridin-2-yl]amino]benzenesulfonamide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2805 mL | 11.4025 mL | 22.8050 mL | |
| 5 mM | 0.4561 mL | 2.2805 mL | 4.5610 mL | |
| 10 mM | 0.2281 mL | 1.1403 mL | 2.2805 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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