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KY-226 is a novel, selective, orally bioactive and allosteric inhibitor of protein tyrosine phosphatase 1B (PTP1B) with an IC50 of 0.25 μM, and without PPARγ agonist activity. KY-226 exerts anti-diabetic and anti-obesity effects by enhancing insulin and leptin signaling, respectively. KY-226 also protects neurons from cerebral ischemic injury. KY-226 protects neurons from cerebral ischemic injury. KY-226 restores Akt (protein kinase B) phosphorylation and extracellular signal-regulated kinase (ERK) reduction in transient middle cerebral artery occlusion (tMCAO) damage. KY-226 protects BBB integrity by restoration of TJ proteins, an effect partly mediated by Akt/FoxO1 pathway activation.
| Targets |
KY-226 inhibits human protein tyrosine phosphatase 1B (PTP1B) with IC50 = 0.28 μM. [1]
KY-226 also inhibits PTP1B with IC50 = 0.25 μM (in a different assay). [2] |
|---|---|
| ln Vitro |
In human Manhattan-derived cells (HepG2), KY-226 (0.3-10 μM) enhances insulin synthesis at the phosphorylated insulin receptor (pIR) [1]. The reductions in ZO-1 mRNA and protein levels caused by LPS were reversed by treatment with KY-226 (1 μM; 24 hours; bEnd.3 cells). pAkt (T308) and its downstream target Forkhead protein framework O1 (FoxO1) (S256) are phosphorylated again in bEnd.3 cells by KY-226 [2].
KY-226 (up to 10 μM) had no effect on adipocyte differentiation in rodent preadipocytes (3T3-L1), whereas pioglitazone markedly promoted differentiation. GPDH activities and cellular triglyceride levels were not increased by KY-226. [1] In human hepatoma-derived HepG2 cells, KY-226 (0.3-10 μM) increased the phosphorylated insulin receptor (pIR) produced by insulin. In HepG2 cells overexpressing PTP1B, KY-226 (0.1-10 μM) enhanced insulin-induced pIR levels. [1] In bEnd.3 mouse brain microvascular endothelial cells, lipopolysaccharide (LPS, 1 μg/mL) treatment reduced ZO-1 mRNA and protein levels; KY-226 (1 μM) rescued this reduction. KY-226 restored phosphorylation of Akt (Thr308) and its downstream target FoxO1 (Ser256) in bEnd.3 cells after LPS stimulation. KY-226 also increased ZO-1 promoter activity in a luciferase reporter assay. [2] |
| ln Vivo |
KY-226 (10-30 mg/kg/day; epidermal documentation; daily; for 4 weeks; cosmetic db/db mice) treatment dramatically lowered antibiotic and lipid levels and hemoglobin A1c values, resulting in enhanced body weight [1 ]. KY-226 attenuates the increase in bone hyperplasia in the bone marrow tolerance test. KY-226 will enhance pIR and phosphorylated Akt in myocardial and femoral resection [1].
In db/db mice (type 2 diabetes model), oral administration of KY-226 (10 and 30 mg/kg/day, 4 weeks) significantly reduced plasma glucose and triglyceride levels as well as hemoglobin A1c (HbA1c) values without increasing body weight gain. KY-226 attenuated plasma glucose elevations in the oral glucose tolerance test (OGTT). KY-226 increased pIR and phosphorylated Akt in the liver and femoral muscle. It did not affect non-fasting plasma insulin levels. [1] In high-fat diet (HFD)-induced obese mice, oral administration of KY-226 (30 and 60 mg/kg/day, 4 weeks) decreased body weight gain, total food consumption, and visceral fat volume gain. KY-226 increased phosphorylated STAT3 (pSTAT3) in the hypothalamus. It slightly increased non-fasting plasma glucose at 30 mg/kg only, significantly decreased triglyceride levels at both doses, and slightly decreased leptin levels. KY-226 did not significantly affect fasting glucose or insulin levels, nor did it affect glucose elevations in OGTT. [1] In a transient middle cerebral artery occlusion (tMCAO) mouse model (2 h occlusion, reperfusion), intraperitoneal administration of KY-226 (10 mg/kg, 30 min after reperfusion) ameliorated BBB breakdown as measured by Evans blue leakage, and reduced neurological deficit scores. KY-226 (10 mg/kg) restored the loss of tight junction proteins ZO-1 and occludin in the ischemic brain 24 h after reperfusion, as shown by western blot and immunofluorescence. KY-226 increased ZO-1 mRNA levels in ipsilateral brain. The protective effects on ZO-1 and occludin were blocked by pre-administration of wortmannin (PI3K inhibitor, i.c.v.) or U0126 (ERK inhibitor, i.v.). [2] |
| Enzyme Assay |
PTP1B inhibition was assessed in 100 mM HEPES buffer (pH 7.2) containing human PTP1B enzyme (23.3 ng/mL final), 1 mM dithiothreitol, 1 mM EDTA, and 3 mM p-nitrophenol phosphate (pNPP). The reaction was initiated by pNPP addition, incubated at 37°C for 30 min, and stopped with 1N NaOH. Absorbance of p-nitrophenol was measured at 405 nm. Enzyme activity in the absence of inhibitor was taken as 100%, and IC50 was calculated. KY-226 showed IC50 = 0.28 μM. [1]
PPARγ agonist activity was assessed using COS-1 cells transfected with PPARγ expression vector and a reporter plasmid; cells were treated with compounds for 24 h, and luciferase activity was measured. KY-226 did not exhibit PPARγ agonist activity, whereas farglitazar (full agonist) showed maximal activation. [1] For the second study, PTP1B inhibition was similarly measured, and KY-226 had an IC50 of 0.25 μM. [2] |
| Cell Assay |
Western Blot analysis [1]
Cell Types: bEnd.3 stimulated with LPS Cell Tested Concentrations: 1 μM Incubation Duration: 24 hrs (hours) Experimental Results: Rescued lipopolysaccharide-induced decrease in ZO-1 mRNA and protein levels. HepG2 cells (with or without stable PTP1B overexpression) were seeded at 1×10^6 cells/well on 6-well plates, cultured for 24 h, then serum-starved for 6 h. Cells were treated with KY-226 (0.1-10 μM) for 1 h, followed by insulin (1-100 nM) for 10 min. Cells were lysed, protein concentrations measured by Bradford method, and western blotting performed for IR, pIR, and PTP1B. KY-226 increased pIR/IR ratio. [1] 3T3-L1 preadipocytes were seeded at 1×10^5 cells/well on 24-well plates. Differentiation was induced with medium containing 1 μM dexamethasone and 0.5 mM IBMX for 2 days, followed by 1 ng/mL insulin plus KY-226 (up to 10 μM) or pioglitazone. GPDH activities were measured after 2 days, and cellular triglyceride levels after 4 days. KY-226 did not affect differentiation. [1] bEnd.3 cells were grown in DMEM with 10% FBS and 1% penicillin-streptomycin at 37°C, 5% CO2. For LPS treatment, cells were treated with 1 μg/mL LPS and/or 1 μM KY-226 for 24 h. Western blotting was performed for ZO-1, CD31, Akt, pAkt (Thr308), FoxO1, pFoxO1 (Ser256). Immunofluorescence staining for ZO-1 (green) and DAPI (blue) was performed. For luciferase reporter assay, bEnd.3 cells were transfected with ZO-1 promoter-pGL3 vector and renilla luciferase, then treated with LPS and/or KY-226 for 24 h, and firefly/renilla activity measured. KY-226 rescued LPS-induced ZO-1 reduction and increased promoter activity. The effects were blocked by wortmannin (0.2 μM) or U0126 (2 μM). FoxO1 inhibitor As1842856 (10 nM) enhanced ZO-1 promoter activity. FoxO1 overexpression suppressed ZO-1 promoter activity, which was rescued by KY-226. [2] |
| Animal Protocol |
Animal/Disease Models: Male db/db mice (8-11 weeks old) [1]
Doses: 10 mg/kg and 30 mg/kg Route of Administration: Oral; daily; for 4 weeks Experimental Results: Significant reduction in plasma glucose and Triglyceride levels and hemoglobin A1c values without increasing weight gain. Male db/db mice (8-11 weeks old) were randomly allocated to groups. KY-226 was suspended in 0.5% methylcellulose and administered orally once daily for 4 weeks at doses of 10 and 30 mg/kg/day. Vehicle (0.5% methylcellulose) was used as control. On day 28, non-fasting blood was taken from tail vein 1 h post-administration. After overnight fasting, OGTT (oral glucose 0.5 g/kg) was performed with blood sampling at 0, 30, 60, 90, 120 min. For insulin signaling evaluation, mice were injected with insulin (1 U/kg, i.v.) and euthanized 5 min later; liver and femoral muscle were collected. [1] Male C57BL/6J mice were fed high-fat diet (HFD) for 4 weeks. KY-226 (30 and 60 mg/kg/day) was administered orally for 4 weeks. Body weight, food consumption, and fat volume gains were measured. Non-fasting and fasting plasma glucose, insulin, triglyceride, and leptin levels were assessed. OGTT was performed as above. Hypothalamus was collected for western blot analysis of pSTAT3. [1] Male ICR mice (25-30 g) were subjected to transient middle cerebral artery occlusion (tMCAO) for 2 h using a silicone suture, followed by reperfusion. KY-226 was dissolved in 10% 1-methyl-2-pyrrolidinone, 5% mixed solution (cremophor EL with ethanol 1:1), and ddH2O. KY-226 (1, 10, 30 mg/kg) was administered intraperitoneally 30 min after reperfusion. For inhibitor studies, wortmannin (50 μM, 2 μL/site) was injected into the right lateral ventricle 30 min before ischemia; U0126 (0.5 mg/kg) was injected via tail vein 30 min before ischemia. Evans blue (2% in saline, 4 mL/kg) was injected via tail vein 18 h after reperfusion, and mice were perfused 6 h later; brains were removed for quantification of dye extravasation at 620 nm. Neurological deficit scores were assessed 24 h after reperfusion (scale 0-5). Brain tissues were collected for western blot, immunofluorescence, and RT-PCR. [2] |
| ADME/Pharmacokinetics |
KY-226 showed high oral absorption in mice; Cmax at 30 mg/kg (p.o.) exceeded IC50 values for PTP1B inhibition. [1]
KY-226 has poor blood-brain barrier (BBB) permeability in normal mice, but can penetrate the BBB of mice after ischemic insult. The maximal brain concentration in ischemic mice is more than 0.5 μM, which exceeds the IC50 for PTP1B. [2] |
| Toxicity/Toxicokinetics |
KY-226 did not exhibit toxicity in HFD-induced obese mice at doses up to 60 mg/kg/day for 4 weeks. [1]
In db/db mice, KY-226 did not increase body weight gain (unlike pioglitazone). [1] In tMCAO mice, mortality rates were 15.3% in vehicle group and 9.6% in KY-226-treated group (10 mg/kg i.p.). [2] |
| References |
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| Additional Infomation |
KY-226 binds to allosteric sites (α-3, 6, and 7 helices) in the PTP1B protein and non-competitively inhibits PTP1B activity. [1]
KY-226 has no carboxyl moiety and does not exhibit PPARγ agonist activity, thus PPARγ-mediated adverse effects (edema, obesity, bone loss) are not expected. [1] In db/db mice, KY-226 did not affect non-fasting plasma insulin levels and attenuated glucose elevations in OGTT, suggesting insulin sensitization. [1] In HFD-induced obese mice, KY-226 decreased body weight gain and fat volume gain with increased pSTAT3 in hypothalamus, suggesting anti-obesity effects via enhancement of leptin signaling. [1] In brain ischemia, KY-226 protects BBB integrity by restoring tight junction proteins ZO-1 and occludin through activation of Akt/FoxO1 signaling pathway. The protective effect is partly mediated by PI3K/Akt and ERK pathways. [2] |
| Molecular Formula |
C27H31NO3S2
|
|---|---|
| Molecular Weight |
481.669945001602
|
| Exact Mass |
481.174
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| Elemental Analysis |
C, 67.33; H, 6.49; N, 2.91; O, 9.96; S, 13.31
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| CAS # |
1621673-53-7
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| PubChem CID |
76955652
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| Appearance |
Fluffy white solid powder
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| LogP |
6.7
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| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
4
|
| Rotatable Bond Count |
12
|
| Heavy Atom Count |
33
|
| Complexity |
653
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
CCCCCCS(=O)(=O)NC(=O)C1=CC=C(C=C1)CSCC2=CC=C(C=C2)C3=CC=CC=C3
|
| InChi Key |
MKXMABKUVSOEJF-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C27H31NO3S2/c1-2-3-4-8-19-33(30,31)28-27(29)26-17-13-23(14-18-26)21-32-20-22-11-15-25(16-12-22)24-9-6-5-7-10-24/h5-7,9-18H,2-4,8,19-21H2,1H3,(H,28,29)
|
| Chemical Name |
4-(biphenyl-4-ylmethylsulfanylmethyl)-N-(hexane-1-sulfonyl)benzoylamide
|
| Synonyms |
KY-226 KY 226 KY226
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| HS Tariff Code |
2934.99.9001
|
| 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) |
DMSO : ~250 mg/mL (~519.03 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.32 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.32 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.32 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0761 mL | 10.3806 mL | 20.7611 mL | |
| 5 mM | 0.4152 mL | 2.0761 mL | 4.1522 mL | |
| 10 mM | 0.2076 mL | 1.0381 mL | 2.0761 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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