PS10

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 (K_d= 239 nM) than for Hsp90 (K_d= 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 IC50 & Target: IC50: 0.8 μM (PDK2); 0.76 μM (PDK4); 2.1 μM (PDK3); 21.3 μM (PDK1)^[1] In Vitro: PS10 shows a higher affinity of PS10 for PDK2 (K_d= 239 nM) than for Hsp90 (K_d= 47,000 nM)^[1].
PS10 is less potent than cycloheximide in HeLa cells, it shows an IC₅₀ value of 284 μM?for the growth inhibition and PS10 has low toxicity in cells^[1].
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].