SB525334 has been characterized as a potent and selective inhibitor of the transforming growth factor-beta1 (TGF-beta1) receptor, activin receptor-like kinase (ALK5). SB525334 inhibited ALK5 kinase activity with an IC50 of 14.3nM [1].
In vitro, SB525334 (1μM; 16h) effectively attenuated the TGF-β1-induced epithelial to mesenchymal transition (EMT) in HPMCs[2]. In the presence of TGF-β, treatment of 4T1 tumor cells with SB525334 can reverse the pro-metastatic effect of TGF-β[3]. SB525334 (0, 1.25, 2.5, 5 and 10μM; 72h) can reduce gemcitabine resistance in resistant cells (MiaPaCa2 and AsPC1). Additionally, treatment with SB525334 (20μM; 24h) reduced the activity of the AKT signaling pathway, which plays a crucial role in gemcitabine resistance[4].
In vivo, In a mouse model of peritoneal fibrosis, cotreatment with chlorhexidine gluconate (CG) and SB525334 (20mg/kg/day; 28 days; p.o.) improved peritoneal thickness and fibrosis and restored peritoneal function[2]. In a orthotopic metastasis model, administration of SB525334(1mg/kg, 5mg/kg and 10mg/kg/every other day; 28 days; i.v.) significantly unleashed the antitumor response of infiltrating neutrophils[3].
References:
[1] Grygielko ET, Martin WM, Tweed C, Thornton P, Harling J, Brooks DP, Laping NJ. Inhibition of gene markers of fibrosis with a novel inhibitor of transforming growth factor-beta type I receptor kinase in puromycin-induced nephritis. J Pharmacol Exp Ther. 2005 Jun;313(3):943-51.
[2] Heo JY, Do JY, Lho Y, Kim AY, Kim SW, Kang SH. TGF-β1 Receptor Inhibitor SB525334 Attenuates the Epithelial to Mesenchymal Transition of Peritoneal Mesothelial Cells via the TGF-β1 Signaling Pathway. Biomedicines. 2021 Jul 19;9(7):839.
[3] Li Y, Hu Q, Li W, Liu S, Li K, Li X, Du J, Yu Z, Wang C, Zhang C. Simultaneous blockage of contextual TGF-β by cyto-pharmaceuticals to suppress breast cancer metastasis. J Control Release. 2021 Aug 10;336:40-53.
[4] Kim YJ, Hwang JS, Hong YB, Bae I, Seong YS. Transforming growth factor beta receptor I inhibitor sensitizes drug-resistant pancreatic cancer cells to gemcitabine. Anticancer Res. 2012 Mar;32(3):799-806.
SB525334已被鉴定为一种高效且选择性的转化生长因子β1（TGF-β1）受体、活化素受体样激酶（ALK5）抑制剂。SB525334对ALK5激酶活性的IC50为14.3nM[1]。
在体外实验中，SB525334（1μM; 16h）有效减轻了TGF-β1诱导的腹膜间皮细胞（HPMCs）的上皮-间充质转化（EMT）[2]。在TGF-β存在时，用SB525334处理4T1肿瘤细胞，可逆转TGF-β的促转移作用[3]。SB525334（0, 1.25, 2.5, 5和10μM; 72h）能够降低耐药细胞（MiaPaCa2和AsPC1）对吉西他滨的耐药性。此外，SB525334（20μM; 24h）的处理降低了AKT信号通路的活性，而该通路在吉西他滨耐药中起着关键作用[4]。
在体内实验中，在腹膜纤维化小鼠模型中，联合使用氯己定葡萄糖酸盐（CG）和SB525334（20mg/kg/天; 28天; 口服）能够改善腹膜厚度和纤维化，并恢复腹膜功能[2]。在乳腺癌原位转移模型中，SB525334（1mg/kg, 5mg/kg和10mg/kg/每隔一天给药; 28天; 静脉注射）的给药显著增强了浸润性中性粒细胞的抗肿瘤反应[3]。