SR1078 is a selective agonist of the retinoic acid receptor-related orphan receptors α and γ (RORα/RORγ). It binds directly to the ligand-binding domain of RORα and RORγ, enhancing their transcriptional activity and thereby stimulating the transcription of RORα/γ target genes[1][2].
体内研究
Pharmacokinetic studies of SR1078 in mice reveal significant exposure levels. After a single 10 mg/kg intraperitoneal injection, plasma concentrations reach 3.6 µM within 1 hour and maintain levels above 800 nM for up to 8 hours, validating the compound's efficacy for in vivo gene expression studies. Two hours post-injection, SR1078 significantly stimulates the expression of G6Pase and FGF21 genes in the liver[1].
SR1078 administered at a dose of 10 mg/kg intraperitoneally leads to a significant 25% reduction in repetitive grooming behavior in BTBR mice[2].
体外研究
SR1078, a synthetic ligand for RORα/RORγ, alters the conformation of RORγ in biochemical assays and activates transcription driven by RORα and RORγ. SR1078 also boosts the expression of endogenous ROR target genes in HepG2 cells expressing these receptors. In cell-based assays using a chimeric receptor with the Gal4 DNA-binding domain and NR ligand-binding domain, SR1078 significantly diminishes the constitutive transactivation activities of RORα and RORγ, while not affecting FXR, LXRα, and LXRβ activities. Treatments with SR1078 at 10 µM notably enhance transcriptional activity in RORα and RORγ cotransfection assays[1].
SR1078 administered at concentrations between 2-10 µM over 24 hours results in a dose-dependent increase in the expression of genes such as A2BP1, CYP19A1, NLGN1, and IPTR1 in SH-SY5Y cells, with EC50s around 3-5 µM[2].
作用机制
SR1078 plays its role by directly binding to the ligand binding domain of RORα and RORγ and increases the transcriptional activity of these receptors, leading to stimulation of RORα/γ target gene transcription.
SR-1078 细胞实验
Cell Line
Concentration
Treated Time
Description
References
MYCN3 cells
5 µM
24 hours
Restoration of BMAL1 mRNA and protein levels
Nat Commun. 2021 Jun 28;12(1):4006.
SK-N-BE(2)-C cells
10 µM
24 hours
Activation of RORα target genes (G6Pase, FGF-21, and BMAL1) transcription
Nat Commun. 2021 Jun 28;12(1):4006.
LAN5 cells
10 µM
24 hours
Activation of RORα target genes (G6Pase, FGF-21, and BMAL1) transcription
Nat Commun. 2021 Jun 28;12(1):4006.
HEK293 cells
10 µM
24 hours
To assess the potential activity of SR1078 on RORβ. Results showed that SR1078 had no activity on RORβ at 10 μM but significantly enhanced the activity of RORα and RORγ.
ACS Chem Neurosci. 2016 Feb 17;7(2):143-8.
SH-SY5Y cells
2, 4, 6, 8, 10 µM
24 hours
To evaluate the effect of SR1078 on the expression of ASD-associated genes. Results showed that SR1078 dose-dependently increased the expression of A2BP1, CYP19A1, NLGN1, and IPTR1, with EC50s in the range of 3-5 μM.
ACS Chem Neurosci. 2016 Feb 17;7(2):143-8.
HepG2 cells
10 µM
24 hours
SR1078 treatment resulted in a significant 3-fold increase in FGF21 mRNA expression. G6Pase mRNA expression was also significantly stimulated ~2-fold by SR1078 treatment.
ACS Chem Biol. 2010 Nov 19;5(11):1029-34.
HEK293 cells
10 µM
24 hours
SR1078 significantly inhibited the constitutive transactivation activity of ROR α and ROR γ, but had no effect on the activity of FXR, LXR α and LXR β.
ACS Chem Biol. 2010 Nov 19;5(11):1029-34.
SK-N-AS MYCN-ER cells
5 µM
72 hours
Inhibition of MYCN-mediated lipid metabolism
Nat Commun. 2021 Jun 28;12(1):4006.
Human chondrocytes
1 µM
48 hours
SR1078 treatment led to decreased expression of COL2A1 and SOX9, and promoted the expression of MMP13, ADAMTS4, and ADAMTS5
Cell Death Dis. 2021 Sep 28;12(10):886.
Huh7 cells
10 µM
Overnight
To test the effect of SR1078 on MIR122 promoter activity, it was found that SR1078 could induce MIR122 promoter activity.
Gastroenterology. 2020 Sep;159(3):999-1014.e9.
SR-1078 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
BTBR mice
Autism model
Intraperitoneal injection
10 mg/kg
Once daily for two weeks
To evaluate the effect of SR1078 on behavior in an autism model. Results showed that SR1078 significantly reduced repetitive grooming behavior in BTBR mice (25% reduction) and increased the expression of ASD-associated genes.
ACS Chem Neurosci. 2016 Feb 17;7(2):143-8.
Mice
C57BL6 mice
Intraperitoneal injection
10 mg/kg
Single injection
SR1078 treatment significantly stimulated the expression of FGF21 and G6Pase in the liver.
ACS Chem Biol. 2010 Nov 19;5(11):1029-34.
Nude mice
LAN5 cell xenograft model
Intraperitoneal injection
15 mg/kg
Once daily for 14 days
Significant inhibition of tumor growth and restoration of BMAL1 protein levels
Nat Commun. 2021 Jun 28;12(1):4006.
C57BL/6 mice
High-fat diet-induced fatty liver model
Intraperitoneal injection
7.5 mg/kg
Twice a week for 3 weeks
To evaluate the therapeutic effect of RS-2982 on fatty liver, the results showed that RS-2982 significantly reduced hepatic steatosis, inflammation, and fibrosis, and improved insulin resistance and weight gain.
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