SB505124 is a selective inhibitor of TGF-β Receptor type I receptors (ALK4, ALK5, ALK7), with IC50 values of 129nM and 47nM for ALK4, ALK5, respectively[1]. SB505124 can inhibit the Wnt and TGF-β1 signaling pathways, reduce inflammatory responses, and decrease the levels of fibrosis markers (such as collagen, α-SMA and fibronectin)[2]. SB505124 has been widely used to inhibit the differentiation of Th17 cells and regulate inflammation in mouse models of arthritis[3].
In vitro, SB505124 treatment at 3μM for 10 days significantly inhibited the osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs), reduced the formation of mineralized matrix, and downregulated osteogenic-related genes[4]. Treatment with SB505124 (2.5μM) for 24 hours significantly enhanced the sensitivity of doxorubicin (DTX)-resistant DU 145 cells to DTX and induced cell death[5]. Pretreatment of rabbit conjunctival submucosal fibroblasts with 10µM SB505124 for 1 hour significantly reduced the level of pSmad2 induced by TGF-β2 as well as the expressions of CTGF and α-SMA[6].
In vivo, SB505124 treatment via intraperitoneal injection at a dose of 10mg/kg once every 12 hours for 5 days alleviated the extent of tertiary neurodegeneration and blood-brain barrier dysfunction in the perinatal mouse model with hypoxic-ischemic brain injury, and improved sensory-motor deficits[7]. SB505124 treatment for 2 weeks (5mg/kg/day; i.p.) caused the increase of erythrocytes in the peripheral blood and the normalized proportion of erythroblast cell clusters in the Lewis lung carcinoma (LLC) cell-xenograft mouse models[8].
References:
[1] Byfield S D C, Major C, Laping N J, et al. SB-505124 is a selective inhibitor of transforming growth factor-β type I receptors ALK4, ALK5, and ALK7[J]. Molecular pharmacology, 2004, 65(3): 744-752.
[2] Tang Y, Liu J, Liu L. Angiotensin-converting Enzyme 2 Suppresses Pulmonary Fibrosis Associated with Wnt and TGF-β1 Signaling Pathways[J]. Discovery medicine, 2024, 36(190): 2274-2286.
[3] Aarts J, Van Caam A, Helsen M, et al. Ab0082 Inhibition Of Tgfβ Signaling Using Sb-505124 Blocks Th17 Differentiation And Restores The Th17/Treg Balance In Vivo, But Does Not Suppress Experimental Arthritis[J]. Annals of the Rheumatic Diseases, 2020, 79: 1341.
[4] Almuraikhi N. Inhibition of TGF‐β type I receptor by SB505124 down‐regulates osteoblast differentiation and mineralization of human mesenchymal stem cells[J]. Cell Biochemistry and Function, 2023, 41(5): 564-572.
[5] Li Y, Zhang B, Xiang L, et al. TGF-β causes docetaxel resistance in prostate cancer via the induction of Bcl-2 by acetylated KLF5 and protein stabilization[J]. Theranostics, 2020, 10(17): 7656.
[6] Sapitro J, Dunmire J J, Scott S E, et al. Suppression of transforming growth factor-β effects in rabbit subconjunctival fibroblasts by activin receptor-like kinase 5 inhibitor[J]. Molecular Vision, 2010, 16: 1880.
[7] Kanal H D, Levison S W. Neuroprotective effects of delayed TGF-β1 receptor antagonist administration on perinatal hypoxic-ischemic brain injury[J]. Developmental Neuroscience, 2024, 46(3): 188-200.
[8] Wang B, Wang Y, Chen H, et al. Inhibition of TGFβ improves hematopoietic stem cell niche and ameliorates cancer-related anemia[J]. Stem Cell Research & Therapy, 2021, 12(1): 65.
SB505124是一种选择性TGF-β I型受体（ALK4、ALK5、ALK7）抑制剂，对ALK4和ALK5的IC50值分别为129nM和47nM[1]。SB505124能够抑制Wnt和TGF-β1信号通路，减轻炎症反应，并降低纤维化标志物（如胶原蛋白、α-SMA和纤连蛋白）的水平[2]。SB505124已被广泛用于抑制Th17细胞分化，并在关节炎小鼠模型中调节炎症[3]。
在体外，使用3µM的SB505124处理10天，显著抑制了人骨髓间充质干细胞（hBMSCs）的成骨分化，减少了矿化基质的形成，并下调了成骨相关基因的表达[4]。使用2.5µM的SB505124处理24小时，显著增强了doxorubicin（DTX）耐药的DU 145细胞对DTX的敏感性，并诱导细胞死亡[5]。用10µM的SB505124预处理兔结膜黏膜下成纤维细胞1小时，显著降低了TGF-β2诱导的pSmad2水平以及CTGF和α-SMA的表达[6]。
在体内，在围产期缺氧缺血性脑损伤小鼠模型中，每隔12小时腹腔注射一次10mg/kg剂量的SB505124，持续5天，减轻了三级神经退行性病变和血脑屏障功能障碍的程度，并改善了感觉运动缺陷[7]。SB505124治疗2周（5mg/kg/day; i.p.）导致了Lewis lung carcinoma (LLC)细胞异种移植小鼠模型中外周血红细胞数量的增加，并使成红细胞簇的比例恢复正常化[8]。