CM-4620 is a selective inhibitor of Orai channels, with IC50 = 0.119μM for Orai1 and 0.895μM for Orai2[1]. CM-4620 could inhibit the activation of the cell death pathway by inhibiting Store-operated Ca2+ entry (SOCE)[2]. CM-4620 has been widely used to alleviate acute pancreatitis in mouse models[3].
In vitro, CM-4620 (2μM) treatment for 72 hours resulted in upregulation of the expression of genes involved in gluconeogenesis, glycolysis, citric acid cycle, carbohydrate metabolism, respiratory electron transport, and endoplasmic reticulum stress within mouse cardiac fibroblasts (CFs), without affecting cell proliferation[4]. Pretreatment of pancreatic acinar cells (PAC) with 1µM CM-4620 for 30min resulted in a significant decrease in Ca2+ influx and prevented palmitic acid-induced cell necrosis[5]. Treatment of Duchenne muscular dystrophy (DMD) patient-derived induced pluripotent stem cells (iPSCs) with 1µM of CM-4620 for one hour inhibited Ca2+ overload and reduced peak Ca2+ levels[6].
In vivo, CM-4620 treatment via continuous intravenous infusion at a dose of 20mg/kg for 4 hours improved cerulein-induced acute pancreatitis and inhibited cell death signaling activation in rats[7]. Intraperitoneal injection of CM-4620 (20mg/kg) every 12 hours for a day reduced systemic inflammatory response in a mouse model of lipopolysaccharide-induced sepsis[8].
References:
[1] Rubaiy H N. ORAI Calcium channels: Regulation, function, pharmacology, and therapeutic targets[J]. Pharmaceuticals, 2023, 16(2): 162.
[2] Liang X, Zhang N, Pan H, et al. Development of store-operated calcium entry-targeted compounds in cancer[J]. Frontiers in pharmacology, 2021, 12: 688244.
[3] Bhardwaj R, Parekh A B. CRAC channels and patho-physiology of peripheral organ systems[J]. Biochemical Society Transactions, 2025: BST20253062.
[4] Pantoja Newman P S, Bajwa A, De Mario A, et al. Orai channel pharmacological manipulation reduces metabolic flexibility in cardiac fibroblasts[J]. American Journal of Physiology-Cell Physiology, 2025, 328(6): C1880-C1892.
[5] Lewis S, Evans D L, Tsugorka T T, et al. Combination of the CRAC channel inhibitor CM4620 and galactose as a potential therapy for acute pancreatitis[J]. Function, 2024, 5(4): zqae017.
[6] Skopin A Y, Glushankova L N, Gusev K O, et al. Vulnerability of Store-Operated Calcium Entry to Inhibitors and Microenvironment in Cells of Different Breast Cancer Subtypes[J]. Life, 2024, 14(3): 357.
[7] Waldron R T, Chen Y, Pham H, et al. The Orai Ca2+ channel inhibitor CM4620 targets both parenchymal and immune cells to reduce inflammation in experimental acute pancreatitis[J]. The Journal of physiology, 2019, 597(12): 3085-3105.
[8] Mei W, Zhang X, Niu M, et al. Deletion of myeloid-specific Orai1 calcium channel does not affect pancreatic tissue damage in experimental acute pancreatitis[J]. Pancreatology, 2024, 24(4): 528-537.