CAY10594 is an orally active phospholipase D2 (PLD2) inhibitor (IC50=140nM). CAY10594 inhibits tumor cell invasion and migration by suppressing PLD2 enzyme activity and reducing phosphatidic acid production. CAY10594 reduces inflammation through regulation of the phosphorylated GSK-3β/JNK axis. CAY10594 can be used in research related to breast cancer, acute liver injury and colitis[1-4].
In vitro, treatment with 10 μM CAY10594 for 1 hour or 3 hours in HEp-2, U-2 OS, PC-3 and CaCo-2 cells inhibited phospholipase D activity, caused elevated diacylglycerol and phosphatidylglycerol levels, enlarged endosomes with tubular structures, and enhanced clathrin-independent retrograde transport[5]. Treatment of human RPMI 8226 cells with 10 μM CAY10594 for 5-15 minutes followed by ATP stimulation inhibited ATP-induced CD23 shedding and blocked ATP-induced ethidium entry into RPMI 8226 cells[6]. Pre-treatment of C2C12 cells with 10 μM CAY10594 for 20 minutes followed by co-treatment with 100 mM ethanol for 50 minutes prevented ethanol-induced Akt phosphorylation and blocked ethanol-induced increase in Rictor binding to mTOR[7].
In vivo, daily oral gavage of 4 mg/kg CAY10594 for 10 consecutive days in DSS-induced C57BL/6 mice improved survival rate, reduced body weight loss and bloody stool severity, and lowered pathological scores[8]. A single intraperitoneal injection of 8 mg/kg CAY10594 in C57BL/6 mice 30 minutes before acetaminophen challenge (500 mg/kg; oral gavage) blocked acetaminophen-induced acute liver injury, reduced hepatic necrosis and hepatocyte apoptosis, and decreased serum AST and ALT levels[9].
References:
[1] Roy A, Derakhshan F, Wilson RJ. Stress peptide PACAP engages multiple signaling pathways within the carotid body to initiate excitatory responses in respiratory and sympathetic chemosensory afferents. Am J Physiol Regul Integr Comp Physiol. 2013 Jun 15;304(12):R1070-84.
[2] Park SY, Kang HM, Oh JW, et al. Cucurbitacin B-, E-, and I-Induced Browning of White Adipocytes Is Promoted by the Inhibition of Phospholipase D2. Int J Mol Sci. 2022 Dec 6;23(23):15362.
[3] Obata Y, Natsume M, Shiina I, et al. Golgi retention of KIT in gastrointestinal stromal tumour cells is phospholipase D activity-dependent. Sci Rep. 2025 Aug 6;15(1):28778.
[4] Choudhary V, Olala LO, Qin H, et al. Aquaporin-3 re-expression induces differentiation in a phospholipase D2-dependent manner in aquaporin-3-knockout mouse keratinocytes. J Invest Dermatol. 2015 Feb;135(2):499-507.
[5] Lingelem ABD, Kavaliauskiene S, Halsne R, et al. Diacylglycerol kinase and phospholipase D inhibitors alter the cellular lipidome and endosomal sorting towards the Golgi apparatus. Cellular and Molecular Life Sciences. 2021;78(3):985-1009.
[6] Pupovac A, Stokes L, Sluyter R, et al. CAY10593 inhibits the human P2X7 receptor independently of phospholipase D1 stimulation. Purinergic Signalling. 2013 Sep;9(3):609-19.
[7] Hong-Brown LQ, Brown CR, Navaratnarajah M, et al. Activation of AMPK/TSC2/PLD by alcohol regulates mTORC1 and mTORC2 assembly in C2C12 myocytes. Alcohol Clin Exp Res. 2013 Nov;37(11):1879-92.
[8] Zhou G, Yu L, Yang W, et al. Blockade of PLD2 ameliorates intestinal mucosal inflammation of inflammatory bowel disease. Mediators of Inflammation. 2016;2016:Article ID 2543070.
[9] Lee SK, Bae GH, Kim YS, et al. A phospholipase D2 inhibitor, CAY10594, ameliorates acetaminophen-induced acute liver injury by regulating the phosphorylated-GSK-3β/JNK axis. Scientific Reports. 2019 May 10;9:7242.