SAG 21k is a potent and orally bioavailable Hedgehog signaling activator with an EC50 value of 0.4nM [1]. SAG 21k can induce a myofibroblast-like phenotype and promote the increased expression of α-smooth muscle actin (αSMA) and type I collagen (Col I) in the extracellular matrix[2]. SAG 21k has been widely used in mouse models to inhibit the formation of intramuscular fat and promote regenerative muscle growth[3].
In vitro, SAG 21k treatment (1μM) for 24h significantly induced the upregulation of Hedgehog response genes (Bmp4, Gli1, Gli2, Hhip, Ptch1, Ptch2) in Trastuzumab-resistant SKBR3 and HCC1954 cells, and promoted the expression of Nanog, Sox2, Bmi1 and Oct4[4]. The 24-hour treatment of 10nM SAG 21k promoted the migration of endoneurial fibroblasts and increased the expression of VEGF-A[5].
In vivo, SAG 21k treatment via intraperitoneal injection at a dose of 5mg/kg/day for one week promoted bone formation in segmental bone defects of mice and increased bone volume[6]. Daily intraperitoneal injection of SAG 21k (0.5mg/kg) twice a day for one week can alleviate the acute colitis induced by dextran sulfate sodium (DSS) in mice and increase the survival rate of the mice[7].
References:
[1] Brunton S A, Stibbard J H A, Rubin L L, et al. Potent agonists of the Hedgehog signaling pathway[J]. Bioorganic & medicinal chemistry letters, 2009, 19(15): 4308-4311.
[2] Lee J J, Perera R M, Wang H, et al. Stromal response to Hedgehog signaling restrains pancreatic cancer progression[J]. Proceedings of the National Academy of Sciences, 2014, 111(30): E3091-E3100.
[3] Liu X, Choi J, Moussa A, et al. Abstract Tu0084: Cilia-dependent Hedgehog Signaling Act as A Guardian against Limb Ischemia-induced Fatty Fibrosis[J]. Arteriosclerosis, Thrombosis, and Vascular Biology, 2025, 45(Suppl_1): ATu0084-ATu0084.
[5] Faniku C, Kong W, He L, et al. Hedgehog signaling promotes endoneurial fibroblast migration and Vegf-A expression following facial nerve injury[J]. Brain research, 2021, 1751: 147204.
[4] Er I, Boz Er A B. Hedgehog pathway is a regulator of stemness in HER2-positive trastuzumab-resistant breast cancer[J]. International Journal of Molecular Sciences, 2024, 25(22): 12102.
[6] Rundle C H, Gomez G A, Pourteymoor S, et al. Sequential application of small molecule therapy enhances chondrogenesis and angiogenesis in murine segmental defect bone repair[J]. Journal of Orthopaedic Research®, 2023, 41(7): 1471-1481.
[7] Lee J J, Rothenberg M E, Seeley E S, et al. Control of inflammation by stromal Hedgehog pathway activation restrains colitis[J]. Proceedings of the National Academy of Sciences, 2016, 113(47): E7545-E7553.
SAG 21k是一种强效且口服生物可利用的Hedgehog信号通路激活剂，EC50值为0.4nM[1]。SAG 21k能够诱导肌成纤维细胞样表型，并促进细胞外基质中α-平滑肌肌动蛋白和I型胶原蛋白表达的增加[2]。SAG 21k已被广泛用于小鼠模型中，以抑制肌内脂肪形成并促进再生性肌肉生长[3]。
在体外，使用1μM的SAG 21k处理耐曲妥珠单抗的SKBR3和HCC1954细胞24小时，显著诱导了 Hedgehog反应基因的上调，并促进了Nanog、Sox2、Bmi1和Oct4的表达[4]。用10nM的SAG 21k处理 24小时，促进了endoneurial成纤维细胞的迁移，并增加了VEGF-A的表达[5]。
在体内，每日腹腔注射5mg/kg剂量的SAG 21k，持续一周，促进了小鼠节段性骨缺损的骨形成并增加了骨体积[6]。每日腹腔注射SAG 21k（0.5mg/kg）两次，持续一周，可减轻葡聚糖硫酸钠(DDS)诱导的小鼠急性结肠炎，并提高小鼠的存活率[7]。