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.