PS10 是一种新型，有效且具有 ATP 竞争性的广谱 PDK 抑制剂，可抑制所有 PDK 同工型，对 PDK2，PDK4，PDK1 和 PDK3 的 IC50 分别为 0.8 μM，0.76 μM，2.1 μM 和 21.3 μM。 PS10 对 PDK2 (Kd= 239 nM) 的亲和力高于对 Hsp90 (Kd= 47 μM)。 PS10 改善葡萄糖耐量，刺激饮食引起的肥胖症中的心肌碳水化合物氧化。 PS10 具有研究糖尿病性心肌病的潜力。
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
PS10 shows a higher affinity of PS10 for PDK2 (Kd= 239 nM) than for Hsp90 (Kd= 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].
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]
[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. [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.
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