EMD638683 is a selective serum and glucocorticoid-induced kinase 1 (SGK1) inhibitor (IC50=3μM)[1]. EMD638683 can reduce the phosphorylation levels of mTOR and 4EBP1, thereby regulating cell proliferation and survival[2]. EMD638683 has antitumor capabilities[3]. EMD638683 also has the effect of protecting cardiac function[4].
In vitro, co-treatment of MCF-7 breast cancer cells with EMD638683 (50μM) and Testosterone albumin conjugates (100nM) for 24 hours significantly enhanced apoptosis and further activated Caspase-3 activity[5]. Pretreatment of HK-2 human renal tubular epithelial cells stimulated by high glucose (30mmol/L) with EMD638683 (50μM) for 72 hours significantly inhibited SGK1 phosphorylation and the NLRP3/caspase-1/GSDMD-N-mediated pyroptosis pathway, reduced the production of pro-inflammatory factors, and high glucose-induced apoptosis[6].
In vivo, EMD638683 (20mg/kg) was administered orally once daily to pretreat rats with Monocrotaline (MCT; 60mg/kg)-induced pulmonary arterial hypertension (PAH). EMD638683 significantly inhibited the activity of SGK1, alleviated the increase in right ventricular systolic pressure (RVSP) and the right ventricular hypertrophy index (RVHI), and improved MCT-induced pulmonary vascular remodeling[7]. EMD638683 (600mg/kg/day) was continuously fed to wild-type mice with chemically induced colon cancer by intraperitoneal injection of 1,2-dimethylhydrazine (DMH; 20mg/kg) combined with dextran sulfate sodium (DSS) in drinking water. EMD638683 significantly inhibited the growth of colon tumors, reduced the number of tumors, and increased colon length[8].
References:
[1] Ackermann TF, Boini KM, Beier N, et al. EMD638683, a novel SGK inhibitor with antihypertensive potency. Cell Physiol Biochem. 2011;28(1):137-46.
[2] Schmid E, Stagno MJ, Yan J, et al. Serum and Glucocorticoid Inducible Kinase 1-Sensitive Survival, Proliferation and Migration of Rhabdomyosarcoma Cells. Cell Physiol Biochem. 2017;43(3):1301-1308.
[3] Schmidt S, Liu G, Liu G, et al. Enhanced Orai1 and STIM1 expression as well as store operated Ca2+ entry in therapy resistant ovary carcinoma cells. Oncotarget. 2014 Jul 15;5(13):4799-810.
[4] Wester M, Heller A, Gruber M, et al. Glucocorticoid stimulation increases cardiac contractility by SGK1-dependent SOCE-activation in rat cardiac myocytes. PLoS One. 2019 Sep 9;14(9):e0222341.
[5] Liu G, Honisch S, Liu G, et al. Inhibition of SGK1 enhances mAR-induced apoptosis in MCF-7 breast cancer cells. Cancer Biol Ther. 2015;16(1):52-9.
[6] Shi X, Zou W, Li X, et al. SGLT2 inhibition attenuates diabetic tubulopathy by suppressing SGK1-mediated pyroptosis. Front Endocrinol (Lausanne). 2025 Sep 15;16:1620230.
[7] Xi X, Liu S, Shi H, et al. Serum-glucocorticoid regulated kinase 1 regulates macrophage recruitment and activation contributing to monocrotaline-induced pulmonary arterial hypertension. Cardiovasc Toxicol. 2014 Dec;14(4):368-78.
[8] Towhid ST, Liu GL, Ackermann TF, et al. Inhibition of colonic tumor growth by the selective SGK inhibitor EMD638683. Cell Physiol Biochem. 2013;32(4):838-48.
EMD638683是一种选择性血清和糖皮质激素诱导的蛋白激酶1（SGK1）抑制剂（IC50=3μM）[1]。EMD638683可降低mTOR和4EBP1的磷酸化水平，从而调控细胞增殖与存活[2]。EMD638683具有抗肿瘤的能力[3]。EMD638683还具有保护心脏功能的作用[4]。
在体外，EMD638683（50μM）与Testosterone albumin conjugates（100nM）联合处理MCF-7乳腺癌细胞24小时，EMD638683显著增强胞凋亡，并进一步激活Caspase-3活性[5]。EMD638683（50μM）预处理高葡萄糖（30mmol/L）刺激的HK-2人肾小管上皮细胞72小时，显著抑制SGK1磷酸化及NLRP3/caspase-1/GSDMD-N介导的细胞焦亡通路，降低促炎因子的产生，以及高糖诱导的细胞凋亡[6]。
在体内，EMD638683（20mg/kg）每日一次灌胃预处理，用于处理Monocrotaline（MCT；60 mg/kg）诱导的肺动脉高压（PAH）大鼠模型。EMD638683显著抑制了SGK1的活性，减轻了右心室收缩压（RVSP）的升高和右心室肥厚指数（RVHI）的增加，改善了了MCT诱导的肺血管重塑[7]。EMD638683（600mg/kg/day）持续喂养，用于处理经1,2-dimethylhydrazine（DMH；20mg/kg）腹腔注射联合葡聚糖硫酸钠（DSS）饮水诱导的化学致癌野生型小鼠模型。EMD638683显著抑制了结肠肿瘤的生长，减少了肿瘤数量并增加了结肠长度[8]。