| Identification | Back Directory | [Name]
PS10 | [CAS]
1564265-82-2 | [Synonyms]
PS10
PS10,PS-10
2-[(24-Dihydroxyphenyl)sulfonyl]-23-dihydro-1H-isoindole-46-diol
1H-Isoindole-4,6-diol, 2-[(2,4-dihydroxyphenyl)sulfonyl]-2,3-dihydro- | [Molecular Formula]
C14H13NO6S | [MDL Number]
MFCD31814433 | [MOL File]
1564265-82-2.mol | [Molecular Weight]
323.32 |
| Chemical Properties | Back Directory | [Boiling point ]
661.7±65.0 °C(Predicted) | [density ]
1.696±0.06 g/cm3(Predicted) | [storage temp. ]
2-8°C | [solubility ]
DMSO: 2mg/mL, clear | [form ]
Solid | [pka]
7.05±0.35(Predicted) | [color ]
Light yellow to khaki |
| Hazard Information | Back Directory | [Uses]
PS10 is a novel, potent and ATP-competitive pan-PDK inhibitor, inhibits all PDK isoforms with IC50 of 0.8 μM, 0.76 μM, 2.1 μM and 21.3 μM for PDK2, PDK4, PDK1, and PDK3, respectively. PS10 shows high affinity for PDK2 (Kd= 239 nM) than for Hsp90 (Kd= 47 μM)[1]. PS10 improves glucose tolerance, stimulates myocardial carbohydrate oxidation in diet-induced obesity. PS10 has the potential for the investigation of diabetic cardiomyopathy[2].PDK: pyruvate dehydrogenase kinase | [Biological Activity]
2-[(2,4-dihydroxyphenyl) sulfonyl]isoindoline-4,6-diol (PS10) can be considered as a therapeutic method to preserve glucose and lipid homeostasis in obesity and type 2 diabetes (T2D). It can induce pyruvate dehydrogenase complex (PDC) activity in liver and kidney. It is also considered as an effective PDK inhibitor to tre at diabetic cardiomyopathy. In the normal myocardiumPS10 helps to enhance fractional carbohydrate oxidation.''PS10 is a potent and selective PDK (Pyruvate dehydrogenase kinase) inhibitor th at improves glucose tolerance and lessens hepatic steatosis in diet-induced obese mice. PS10 binds to the ATP-binding pocket of PDKs. | [Enzyme inhibitor]
This novel ATP binding pocket-directed inhibitor (FW = 323.32 g/mol), systematically named 2-[(2,4-dihydroxyphenyl)sulfonyl]isoindoline-4,6- diol, targets all four PDK isoforms, with an IC50 = 0.8 μM and Ki = 0.24 μM for PDK2. Its design is based on structure-guided design, converting a known Hsp90 inhibitor into a series of highly specific PDK inhibitors, substituting a sulfonyl group in place of a carbonyl in the parent compound. This modification results in weak binding to Hsp90 (Ki = 47 μM). PS10 administration (70 mg/kg) to diet-induced obese mice significantly augments PDC activity with reduced phosphorylation in different tissues. Prolonged treatment improves glucose tolerance, with notably lessened hepatic steatosis in a mouse model. Such findings suggest pharmacological targeting of PDK may be useful in controlling glucose and fat levels in obesity and type 2 diabetes. | [in vivo]
PS10 (Intraperitoneal injection; 70 mg/kg; single dose) treatment lead to 11- and 23-fold higher PDC activity in heart and liver, respectively. Meanwhile, there results in a 1.4-fold enhancement of PDC activity in kidneys compared with vehicle-group[1].PS10 (Intraperitoneal injection; 70 mg/kg; 3 days) treatment results that thePDC activity profiles and the phospho-E1α subunit level is similar to the single-dose. Notably, the three-day treatment attenuates the enhancement of PDK activity in heart[1].PS10 (intraperitoneal injection; 70 mg/kg; 4 weeks) is treated in mice and subjected to a glucose tolerance test. when challenged with 1.5 g/kg glucose, the plasma glucose level in the vehicle-treated control is at 200 mg/dl at 0 min, peaks at 482 mg/dl at 30 min, and reduces to 210 mg/dl at 120 min. In PS10-treated DIO mice, the glucose level at 168 mg/dl at 0 min is lower than that in vehicle-treated animals, reachs 312 mg/dl at 30 min, and returns to 163 mg/dl at 120 min[1].PS10 (intraperitoneal injection; 70 mg/kg) and DCA both stimulates flux through PDC as measured by the appearance of hyperpolarized [13C]bicarbonate. It shows similar glucose tolerance response to glucose challenge restores PDC activity in the DIO mouse hearts[2]. | Animal Model: | C57BL/6J male mice at 6 to 8 weeks old[2] | | Dosage: | 70 mg/kg/day | | Administration: | Intraperitoneal injection | | Result: | Improved glucose tolerance in the intact animal. |
| [References]
[1] Structure-guided development of specific pyruvate dehydrogenase kinase inhibitors targeting the ATP-binding pocket.J Biol Chem. 2014 Feb 14;289(7):4432-43. DOI:10.1074/jbc.M113.533885
[2] Wu CY, et al. A novel inhibitor of pyruvate dehydrogenase kinase stimulates myocardial carbohydrate oxidation in diet-induced obesity.J Biol Chem. 2018 Jun 22;293(25):9604-9613. DOI:10.1074/jbc.RA118.002838 |
|
| Company Name: |
Merck KGaA
|
| Tel: |
21-20338288 |
| Website: |
www.sigmaaldrich.cn |
|