PS 48 is a PDK1 (phosphoinositide-dependent kinase-1) activator with an AC50 of 8μM[1]. PS 48 can bind to the HM/PIF binding pocket of PDK1, targeting the protein kinase catalytic domain without affecting the ATP binding site[2]. PDK1 is mainly responsible for regulating the activity of the pyruvate dehydrogenase complex (PDH) and is also involved in multiple signaling pathways, especially closely related to the PI3K/AKT signaling pathway[3]. Therefore, PS 48 is often used in research related to mitochondrial function and cell proliferation [4]
In vitro, after 42-44 hours of treatment with PS 48 (10μM) in porcine oocytes, the maturation rate of oocytes was significantly increased, the proportion of the metaphase stage of the second meiosis (MII) oocytes was increased, and the expansion of cumulus cells was improved. In addition, PS 48 significantly upregulated the mRNA and protein levels of maturation-related genes (such as CyclinB1, MOS, Akt, mTOR, BMP15, GDF9, etc.), while reducing the protein level of the pro-apoptotic gene BAX and increasing the expression of the anti-apoptotic gene BCL2[5]. Pre-treatment of MC3T3-E1 cells with PS 48 (5μM) can significantly enhance the osteogenic capacity of osteoblasts inhibited by dexamethasone (Dex), and increase the protein levels of p-AKT and p-mTOR by activating the AKT/mTOR signaling pathway [6].
In vivo, PS 48 (50mg/kg) was administered via diet to APP/PS1 transgenic mice from 10 to 14 months of age. PS 48 significantly improved spatial learning and memory in the Morris Water Maze test in transgenic mice[7]. PS 48 (50mg/kg) was administered via diet to APP/PS1 transgenic mice from 12 to 14 months of age. PS 48 significantly reduced the phosphorylation levels of Tau protein, partially reversed hippocampal atrophy, and improved the phosphorylation state of insulin signaling pathway-related proteins[8].
References:
[1] Hindie V, Stroba A, Zhang H, et al. Structure and allosteric effects of low-molecular-weight activators on the protein kinase PDK1. Nat Chem Biol. 2009 Oct;5(10):758-64.
[2] Han F, Xue M, Chang Y, et al. Triptolide Suppresses Glomerular Mesangial Cell Proliferation in Diabetic Nephropathy Is Associated with Inhibition of PDK1/Akt/mTOR Pathway. Int J Biol Sci. 2017 Sep 21;13(10):1266-1275.
[3] Querfurth H, Marshall J, Parang K, et al. A PDK-1 allosteric agonist neutralizes insulin signaling derangements and beta-amyloid toxicity in neuronal cells and in vitro. PLoS One. 2022 Jan 21;17(1):e0261696.
[4] Mordhorst BR, Kerns KC, Schauflinger M, et al. Pharmacologic treatment with CPI-613 and PS48 decreases mitochondrial membrane potential and increases quantity of autolysosomes in porcine fibroblasts. Sci Rep. 2019 Jul 1;9(1):9417.
[5] Jiao Y, Zhu S, Li J, et al. PS48 promotes in vitro maturation and developmental competence of porcine oocytes through activating PI3K/Akt signalling pathway. Reprod Domest Anim. 2020 Dec;55(12):1678-1687.
[6] Xu WN, Zheng HL, Yang RZ, et al. HIF-1α Regulates Glucocorticoid-Induced Osteoporosis Through PDK1/AKT/mTOR Signaling Pathway. Front Endocrinol (Lausanne). 2020 Jan 28;10:922.
[7] Querfurth H, Slitt A, DiCamillo A, et al. A PDK-1 allosteric agonist improves spatial learning and memory in a βAPP/PS-1 transgenic mouse-high fat diet intervention model of Alzheimer's disease. Behav Brain Res. 2023 Feb 13;438:114183.
[8] Querfurth HW, Lemere C, Ciola J, et al. Target Validation Studies of PS48, a PDK-1 Allosteric Agonist, for the Treatment of Alzheimer's Disease Phenotype in APP/PS1 Transgenic Mice. Int J Mol Sci. 2025 Apr 8;26(8):3473.
PS 48是一种磷酸肌醇依赖性蛋白激酶1（PDK1）活性激活剂，AC50为8μM[1]。PS 48可与PDK1的HM/PIF结合口袋，靶向蛋白激酶催化结构域但不影响ATP结合位点[2]。PDK1主要负责调控丙酮酸脱氢酶复合体（PDH）的活性，同时还参与了多个信号通路，特别是与PI3K/AKT信号通路密切相关[3]。因此，PS 48常被用于线粒体功能以及细胞增殖的相关研究中[4]。
在体外，PS 48（10μM）猪卵母细胞42-44小时后，显著提高了卵母细胞的成熟率，增加了第二次减数分裂中期（MII期）的卵母细胞的比例，并改善了卵丘细胞的扩张。此外，PS 48还显著上调了与成熟相关的基因（如CyclinB1、MOS、Akt、mTOR、BMP15、GDF9等）的mRNA和蛋白水平，同时降低了促凋亡基因BAX的蛋白水平，增加了抗凋亡基因BCL2的表达[5]。PS 48（5μM）预处理MC3T3-E1细胞，能够显著增强地塞米松（Dex）诱导的成骨抑制的骨细胞的成骨能力，同时通过激活AKT/mTOR信号通路增加p-AKT和p-mTOR的蛋白水平[6]。
在体内，PS 48（50mg/kg）通过饮食给药，用于处理APP/PS1转基因小鼠，从10月龄开始直至14月龄。PS 48显著改善了转基因小鼠在Morris水迷宫测试中的空间学习和记忆能力[7]。PS 48（50mg/kg）通过饮食给药，用于处理APP/PS1转基因小鼠，从12月龄开始直至14月龄。PS 48显著减少了Tau蛋白的磷酸化水平，部分逆转了海马体的萎缩，并改善了胰岛素信号通路相关蛋白的磷酸化状态[8]。