SR1078 is an agonist of the retinoic acid receptor-related orphan receptors (RORs) RORα and RORγ, with IC50 values of 1-3µM[1]. SR1078 can directly bind to the ligand binding domains of RORα and RORγ, increasing the transcriptional activity of these receptors, thereby stimulating the transcription of RORα/γ target genes[2, 3]. SR1078 can regulate osteoblast metabolism through anti-inflammatory effects[4].
In vitro, SR1078 (2-10µM) treatment of human neuroblastoma SH-SY5Y cells for 24h increased the expression of A2BP1, CYP19A1, NLGN1 and IPTR1 genes in the cells in a dose-dependent manner, with an EC50 range of 3-5μM[5]. SR1078 (1, 5µM) treatment of HepG2 cells increased the expression of p53 protein and induced cell apoptosis[6].
In vivo, SR1078 (20mg/kg) was intraperitoneally injected into mice bearing colorectal cancer cell xenografts, significantly inhibiting the growth of subcutaneous tumors and the metastasis of tumor cells[7].
References:
[1] Wang Y, Kumar N, Nuhant P, et al. Identification of SR1078, a synthetic agonist for the orphan nuclear receptors RORα and RORγ[J]. ACS chemical biology, 2010, 5(11): 1029-1034.
[2] Kamenecka T M, Lyda B, Chang M R, et al. Synthetic modulators of the retinoic acid receptor-related orphan receptors[J]. MedChemComm, 2013, 4(5): 764-776.
[3] Nematisouldaragh D, Kirshenbaum E, Uzonna M, et al. The Role of Retinoic-Acid-Related Orphan Receptor (RORs) in Cellular Homeostasis[J]. International Journal of Molecular Sciences, 2024, 25(21): 11340.
[4] Fernandes J, Benderdor M, Shi Q. SR1078, A synthetic ligand of nuclear receptor ror alpha, modulates osteoblast metabolism with anti-inflammatory effects[J]. Osteoarthritis and Cartilage, 2012, 20: S115-S116.
[5] Wang Y, Billon C, Walker J K, et al. Therapeutic effect of a synthetic RORα/γ agonist in an animal model of autism[J]. ACS Chemical Neuroscience, 2016, 7(2): 143-148.
[6] Wang Y, Solt L A, Kojetin D J, et al. Regulation of p53 stability and apoptosis by a ROR agonist[J]. PloS one, 2012, 7(4): e34921.
[7] Wang Y N, Ruan D Y, Wang Z X, et al. Targeting the cholesterol-RORα/γ axis inhibits colorectal cancer progression through degrading c-myc[J]. Oncogene, 2022, 41(49): 5266-5278.
SR1078是一种维甲酸受体相关孤儿受体（ROR）RORα和RORγ的激动剂，IC50值均为1-3µM[1]。SR1078能够直接与RORα和RORγ 的配体结合结构域结合，增加这些受体的转录活性，从而刺激RORα/γ靶基因转录[2, 3]。SR1078能够通过抗炎作用调节成骨细胞代谢[4]。
在体外，SR1078（2-10µM）处理人神经母细胞瘤SH-SY5Y细胞24h，以剂量依赖性方式增加了细胞中A2BP1、CYP19A1、NLGN1和IPTR1基因的表达，EC50范围为3-5μM[5]。SR1078（1, 5µM）处理HepG2细胞，增加了p53蛋白的表达，诱导了细胞凋亡[6]。
在体内，SR1078（20mg/kg）通过腹腔注射治疗结直肠癌细胞异种移植小鼠，显著抑制了小鼠皮下肿瘤的生长，抑制了肿瘤细胞的转移[7]。