GW788388

GW788388 is a potent and selective ALK5 inhibitor (IC₅₀=18nM)^[1]. GW788388 also inhibits TGF-β type II receptor (IC₅₀=93nM) and activin type II receptor activity, but does not inhibit BMP type II receptors^[2]. GW788388 can inhibit epithelial-mesenchymal transition in cells^[3], and attenuate left ventricular remodeling and cardiac dysfunction^[4].

In vitro, treatment of dengue virus type 2 (DENV-2)-infected macrophages with GW788388 (0.5–2μM) for 48 hours significantly reduced Smad2 protein phosphorylation levels and decreased TGF-β1 secretion by inhibiting TGF-β type I/II receptors. This enhanced the macrophages' ability to clear the virus, resulting in a dose-dependent reduction in viral load^[5]. Treatment of C2C12 skeletal muscle cells with GW788388 (1–10μM) for 6 days significantly increased the myotube differentiation index and mean nuclear number, enhancing myogenesis^[6].

In vivo, pretreatment of male C57BL/6J mice with GW788388 (1mg/kg, intraperitoneal injection) 1 hour before acetaminophen (600mg/kg) injection significantly alleviated acetaminophen-induced liver necrosis and reduced serum ALT and AST levels. GW788388 also decreased the expression of pro-inflammatory cytokines IL-1β and TNFα, reduced phosphorylated JNK levels and DNA fragmentation in the liver, and promoted hepatocyte proliferation^[7]. Oral administration of GW788388 (2mg/kg/day) for 5 weeks to 6-month-old db/db mice significantly ameliorated diabetic nephropathy-related glomerulosclerosis and renal fibrosis^[8].

References:
[1] Ferreira RR, Abreu RDS, Vilar-Pereira G, et al. TGF-β inhibitor therapy decreases fibrosis and stimulates cardiac improvement in a pre-clinical study of chronic Chagas' heart disease. PLoS Negl Trop Dis. 2019 Jul 31;13(7):e0007602.
[2] Gellibert F, de Gouville AC, Woolven J, et al. Discovery of 4-{4-[3-(pyridin-2-yl)-1H-pyrazol-4-yl]pyridin-2-yl}-N-(tetrahydro-2H- pyran-4-yl)benzamide (GW788388): a potent, selective, and orally active transforming growth factor-beta type I receptor inhibitor. J Med Chem. 2006 Apr 6;49(7):2210-21.
[3] Lho Y, Do JY, Heo JY, et al. Effects of TGF-β1 Receptor Inhibitor GW788388 on the Epithelial to Mesenchymal Transition of Peritoneal Mesothelial Cells. Int J Mol Sci. 2021 Apr 29;22(9):4739.
[4] Tan SM, Zhang Y, Connelly KA, et al. Targeted inhibition of activin receptor-like kinase 5 signaling attenuates cardiac dysfunction following myocardial infarction. Am J Physiol Heart Circ Physiol. 2010 May;298(5):H1415-25.
[5] Teixeira GS, Andrade AA, Torres LR, et al. Suppression of TGF-β/Smad2 signaling by GW788388 enhances DENV-2 clearance in macrophages. J Med Virol. 2022 Sep;94(9):4359-4368.
[6] Levolger S, Wiemer EAC, van Vugt JLA, et al. Inhibition of activin-like kinase 4/5 attenuates cancer cachexia associated muscle wasting. Sci Rep. 2019 Jul 8;9(1):9826.
[7] McMillin M, Grant S, Frampton G, et al. The TGFβ1 Receptor Antagonist GW788388 Reduces JNK Activation and Protects Against Acetaminophen Hepatotoxicity in Mice. Toxicol Sci. 2019 May 1;170(2):549-561.
[8] Petersen M, Thorikay M, Deckers M, et al. Oral administration of GW788388, an inhibitor of TGF-beta type I and II receptor kinases, decreases renal fibrosis. Kidney Int. 2008 Mar;73(6):705-15.

GW788388是一种有效的、选择性ALK5抑制剂（IC₅₀=18nM）^[1]。GW788388还抑制TGF-βII型受体（IC₅₀=93nM）和激活素II型受体的活性，但不抑制BMP II型受体^[2]。GW788388可抑制细胞细胞上皮间质转化^[3]。GW788388还可减弱左心室重塑和心功能障碍^[4]。

在体外，GW788388 (0.5–2μM) 处理登革2型病毒(DENV-2)感染的巨噬细胞48小时，GW788388通过抑制TGF-βI/II型受体，显著降低Smad2蛋白的磷酸化水平，并减少TGF-β1的分泌，增强巨噬细胞对病毒的清除能力，促使病毒载量呈剂量依赖性降低^[5]。GW788388 (1–10μM) 处理C2C12骨骼肌细胞6天，显著提高肌管分化指数和平均核数量，增强肌生成^[6]。

在体内，GW788388 (1mg/kg)在Acetaminophen (600mg/kg) 注射前1小时腹腔注射预处理雄性C57Bl/6J小鼠，GW788388显著减轻了对Acetaminophen诱导的肝坏死和血清ALT、AST升高，减少促炎细胞因子IL-1β和TNFα的表达，降低肝内磷酸化JNK水平和DNA断裂，增强肝细胞增殖^[7]。GW788388 (2mg/kg/day)口服给药5周，用于处理6月龄的db/db小鼠，显著减轻了糖尿病肾病相关的肾小球硬化和肾纤维化^[8]。