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.
CM-4620是一种选择性Orai通道抑制剂，对Orai1和Orai2的IC50值分别为0.119μM和0.895μM[1]。CM-4620通过抑制Store-operated Ca2+ entry (SOCE)阻断细胞死亡通路的激活[2]。CM-4620已广泛应用于小鼠模型以缓解急性胰腺炎[3]。
在体外，2μM的CM-4620处理小鼠心脏成纤维细胞（CFs）72小时可上调糖异生、糖酵解、柠檬酸循环、碳水化合物代谢、呼吸电子传递及内质网应激相关基因的表达，且不影响细胞增殖[4]。1µM的CM-4620预处理胰腺腺泡细胞（PAC）30分钟能显著降低Ca2+内流并预防棕榈酸诱导的细胞坏死[5]。1µM的CM-4620处理杜氏肌营养不良症（DMD）患者来源的诱导多能干细胞（iPSCs）1小时可抑制Ca2+超载并降低峰值钙离子水平[6]。
在体内，大鼠持续静脉输注CM-4620（20mg/kg；4小时）可改cerulein诱导的急性胰腺炎并抑制细胞死亡信号激活[7]。小鼠每12小时腹腔注射CM-4620（20mg/kg）持续一天能减轻脂多糖诱导的脓毒症模型中的全身炎症反应[8]。