EW-7197 is an orally bioavailable inhibitor of the serine/threonine kinase, transforming growth factor (TGF)-beta receptor type 1 (TGFBR1), also known as activin receptor-like kinase 5 (ALK5) with IC50 value of 12.9nM[1]. EW-7197 exerts the anti-inflammatory and anti-fibrotic properties [2][4][5]. EW-7197 has also demonstrated robust antitumor activity across various cancer models, including pancreatic cancer and breast cancer[3][6].
In vitro, pretreated SH-SY5Y neuroblastoma cells with EW-7197 (50nM, 100nM, 150nM) for 24h performed neuroprotective effect on SH-SY5Y against Aβ-induced neurotoxicity. Pretreated BV-2 microglial cells with 100nM EW-7197 for 4h prior to exposure of 2μM Aβ resulted in a significant attenuation in the production of proinflammatory cytokines (TNF-α and IL-1β) compared with the Aβ control group. The results show that EW-7197 could be an alternative approach to selectively modulate Aβ-induced neuroinflammatory responses in microglia of Alzheimer’s disease patients by targeting TGF-β signaling[2]. Pancreatic cancer cell lines MIA PaCa-2 and PANC-1 treated with EW-7197 (10µM) for 72 hours inhibited cell viability and proliferation. The therapeutic effect of EW-7197 on pancreatic cancer was significantly enhanced when applied in combination with gemcitabine (0.1µM) for an additional 48 hours[3]. Hepatocellular fibrosis was induced in human hepatic stellate cells (LX-2) and Alpha mouse liver 12 (AML12) mouse hepatocytes using TGF-β (2ng/mL). The cells were then treated with EW-7197 (0.5μM) for 24h. EW-7197 demonstrated significant anti-fibrotic effects in both LX-2 and AML12 cells, significantly reducing the expression of fibrosis markers (such as α-SMA, Col I, and p-SMAD2/3) induced by TGF-β and partially restoring the activity of Erk and Akt[4].
In vivo, EW-7197 (5mg/kg/day) administered via oral gavage in dextran sulfate sodium (DSS)‐induced colitis mice for 7 days ameliorated colitis clinical symptoms and attenuated histological damage to colon tissue by regulating inflammatory gene expression as well as oxidant/antioxidant balance in colitis mice[5]. EW-7197 (10mg/kg) or vehicle (simulated gastric fluid) was given orally five times a week for 2 weeks into rat Models of Peyronie's Disease (PD). EW-7197 induced significant regression of fibrotic plaques in PD rats in vivo through reduced infiltration of inflammatory cells and reduced expression of phospho-Smad2, which recovered erectile function[6]. EW-7197 (2.5mg/kg) were orally administered into 4T1-Luc allograft BALB/c syngeneic mouse model for two weeks to investigate whether EW-7197 blocks radiation-induced TGF-β signaling in breast cancer. The results showed that EW-7197 treatment overcomed the limitations of radiotherapy in breast cancer treatment by inhibiting oxidative stress, EMT, cancer stem cell (CSC), and fibrosis[7].
References:
[1] Son J Y, Park S Y, Kim S J,et al. EW-7197, a novel ALK-5 kinase inhibitor, potently inhibits breast to lung metastasis. Mol Cancer Ther. 2014 Jul;13(7):1704-16.
[2] Tiong S Q, Mohgan R N, Quek J Y, et al. Inhibition of the Transforming Growth Factor-β Signaling Pathway Confers Neuroprotective Effects on Beta-Amyloid-Induced Direct Neurotoxicity and Microglia-Mediated Neuroinflammation. Neurol Res Int. 2025 Jan 30:2025:8948290.
[3] Lee J E, Lee P, Yoon Y C, et al. EW-7197, TGF-β receptor I inhibitor, augments the sensitization of the anti-cancer activity of gemcitabine in pancreatic cancer. Biomed Pharmacother. 2023 Jun:162:114716.
[4] Ha K B, Lee E S, Park N W, et al. Beneficial Effects of a Curcumin Derivative and Transforming Growth Factor-β Receptor I Inhibitor Combination on Nonalcoholic Steatohepatitis. Diabetes Metab J. 2023 Jul;47(4):500-513
[5] Binabaj M M, Asgharzadeh F, Avan A, et al. EW-7197 prevents ulcerative colitis-associated fibrosis and inflammation. J Cell Physiol. 2019 Jul;234(7):11654-11661.
[6] Song K M, Chung D Y, Choi M J, et al. EW-7197, a Novel, Orally Bioavailable Activin Receptor-Like Kinase 5 Inhibitor, Promotes Regression of Fibrotic Plaques in a Rat Model of Peyronie's Disease. World J Mens Health. 2020 Oct;38(4):552-563.
[7] Park J Y, Choi J W, Cho I Y, Sheen Y Y. Radiotherapy-induced oxidative stress and fibrosis in breast cancer are suppressed by vactosertib, a novel, orally bioavailable TGF-β/ALK5 inhibitor. Sci Rep. 2022 Sep 27;12(1):16104.
EW-7197是一种口服有效的丝氨酸/苏氨酸激酶抑制剂，靶向转化生长因子（TGF）-β受体I（TGFBR1），也称为激活素受体样激酶5（ALK5），其IC50值为12.9nM[1]。EW-7197发挥抗炎和抗纤维化特性[2][4][5]。此外，EW-7197还在多种癌症模型（包括胰腺癌和乳腺癌）中展现出强大的抗肿瘤活性[3][6]。
体外实验中，用EW-7197（50nM、100nM、150nM）预处理SH-SY5Y神经母细胞瘤细胞24小时，对Aβ诱导的神经毒性具有神经保护作用。在BV-2小胶质细胞中，用EW-7197（100nM）预处理4小时后暴露于2μM的Aβ，与Aβ对照组相比，促炎细胞因子（TNF-α和IL-1β）的产生显著减少。结果表明，通过靶向TGF-β信号通路，EW-7197可能是调节阿兹海默患者小胶质细胞中Aβ诱导的神经炎症反应的替代方法[2]。在胰腺癌细胞系MIA PaCa-2和PANC-1细胞中，用10µM的EW-7197处理72小时抑制了细胞活力和增殖。当与gemcitabine（0.1µM）联合应用额外48小时后，EW-7197对胰腺癌的治疗效果显著增强[3]。在人肝星状细胞（LX-2）和小鼠肝细胞（AML12）中，用2ng/mL的TGF-β诱导肝细胞纤维化，然后用0.5μM的EW-7197处理24小时。EW-7197在LX-2和AML12细胞中均显示出显著的抗纤维化效果，显著减少了TGF-β诱导的纤维化标志物（如α-SMA、Col I和p-SMAD2/3）的表达，并部分恢复了Erk和Akt的活性[4]。
体内实验中，用5mg/kg/天的EW-7197通过口服灌胃在葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠模型中给药7天，通过调节炎症基因表达以及结肠炎小鼠的氧化/抗氧化平衡，改善了结肠炎的临床症状并减轻了结肠组织的组织学损伤[5]。在佩罗尼病（PD）大鼠模型中，每周五次口服给予10mg/kg的EW-7197或模拟胃液（vehicle）持续2周。体内实验结果表明，EW-7197通过减少炎症细胞的浸润和降低磷-Smad2的表达，在PD大鼠中诱导了纤维化斑块的显著消退，并恢复了勃起功能[6]。在4T1-Luc同种异体移植BALB/c同系小鼠乳腺癌模型中，口服给予2.5mg/kg的EW-7197持续两周，以研究EW-7197是否阻断乳腺癌中辐射诱导的TGF-β信号通路。结果表明，通过抑制氧化应激、上皮-间质转化（EMT）、癌症干细胞（CSC）和纤维化，EW-7197治疗克服了乳腺癌治疗中放疗的局限性[7]。