SBI-115 is an antagonist of the G protein-coupled bile acid receptor 1 (TGR5; GPCR19)[1]. TGR5 is involved in inflammatory responses, and SBI-115 inhibits TGR5, which can increase the concentration and mRNA expression of pro-inflammatory factors both in vivo and in vitro[2].
In vitro, treatment of cystic cholangiocytes with SBI-115 (100, 200μM) for 24 hours resulted in a reduction of cell numbers by 20%-33% and a decrease in cyclic adenosine monophosphate (cAMP) levels[3]. Treatment of human pancreatic cancer cell lines PANC-1 and BXPC-3 with SBI-115 (1-20μM) for 48 hours showed significant inhibitory activity on PANC-1 and BXPC-3 cells at 10 μM and 5 μM, respectively, leading to morphological changes, a significant increase in vacuoles, and mitochondrial membrane disruption[4].
In vivo, a single intrathecal injection of SBI-115 (15μg) in spared nerve injury (SNI) mice blocked the therapeutic effect of TGR5 agonists on the mechanical hyperalgesia response in mice[5].
References:
[1] Ye D, He J, He X. The role of bile acid receptor TGR5 in regulating inflammatory signalling[J]. Scandinavian Journal of Immunology, 2024: e13361.
[2] Xu J, Cao J, Tan B, et al. G protein-coupled bile acid receptor 1 reduced hepatic immune response and inhibited NFκB, PI3K/AKT, and PKC/P38 MAPK signaling pathway in hybrid grouper[J]. Journal of Animal Science, 2023, 101: skad307.
[3] Masyuk T V, Masyuk A I, Lorenzo Pisarello M, et al. TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases through cyclic adenosine monophosphate/Gαs signaling[J]. Hepatology, 2017, 66(4): 1197-1218.
[4] Lei Y, Li G, Li J, et al. Investigation of the potential role of TGR5 in pancreatic cancer by a comprehensive molecular experiments and the liquid chromatography mass spectrometry (LC–MS) based metabolomics[J]. Discover Oncology, 2022, 13(1): 46.
[5] Wu Y, Qiu Y, Su M, et al. Activation of the bile acid receptors TGR5 and FXR in the spinal dorsal horn alleviates neuropathic pain[J]. CNS Neuroscience & Therapeutics, 2023, 29(7): 1981-1998.
SBI-115是一种G蛋白胆汁酸偶联受体1（TGR5；GPCR19）拮抗剂[1]。TGR5参与炎症反应，SBI-115抑制TGR5，可升高体内或体外促炎因子的浓度和mRNA表达[2]
在体外，SBI-115（100，200μM）处理囊性胆管细胞24 h，使细胞数量减少了20%-33%，降低了环磷酸腺苷（cAMP）水平[3]。SBI-115（1-20μM）处理人胰腺癌细胞株PANC-1和BXPC 3细胞48 h，分别在10 μM和5 μM时对PANC-1和BXPC 3细胞表现出显著的抑制活性，细胞形态学改变，空泡明显增多，线粒体膜破裂[4]。
在体内，SBI-115（15μg）通过单次鞘内注射处理保留神经损伤（SNI）小鼠，阻断了TGR5激动剂对小鼠机械性痛觉超敏反应的治疗效果[5]。