REV-ERBα is a member of the nuclear receptor superfamily that functions as a receptor for the porphoryin heme. REV-ERBα suppresses transcription of its target genes in a heme-dependent manner. SR8278 displays REV-ERBα antagonist activity in contrast to the agonist activity displayed by GSK4112. Addition of SR8278 shows the opposite effect enhancing the expression of the reporter gene presumably due to blocking the action of the endogenous agonist heme. Addition of the antagonist, SR8278, results in inhibition of the REV-ERBα transcriptional repression activity in a dose-dependent manner (EC50=0.47μM). Treatment of HepG2 cells with 10 μM SR8278 for 24 h resulted in a significant increase in the expression of REV-ERBα target genes consistent with the compound blocking the action of the endogenous agonist, heme[1]. Specifically, the values of areas under plasma concentration time curves (AUC), initial plasma concentrations (C0), elimination half-lives (t1/2), and clearances (CL) were 608.33 ± 295.25 vs. 598.59 ± 276.92 ng·h/mL, 2410.25 ± 202.36 vs. 3742.11 ± 1300.21 ng/mL, 0.17 ± 0.08 vs. 0.11 ± 0.04 h, 3330.83 ± 1609.48 vs. 3364.81 ± 1111.38 mL/kg·h for SR8278 in normal rats vs. diabetic rats, respectively[2].
SR8278 细胞实验
Cell Line
Concentration
Treated Time
Description
References
NTERT keratinocytes
10 μM
24 h
SR8278 enhanced BMAL1 activity and reduced HSV-1 infection.
JCI Insight. 2023 Oct 23;8(20):e171548.
HepG2 cells
7.5 µM
24 h
SR8278 significantly inhibited the growth of HepG2 cells
Proc Natl Acad Sci U S A. 2024 Oct 15;121(42):e2411321121.
Hepa1-6 cells
7.5 µM
24 h
SR8278 significantly inhibited the growth of Hepa1-6 cells
Proc Natl Acad Sci U S A. 2024 Oct 15;121(42):e2411321121.
22RV1 cells
7.5 µM
24 h
SR8278 significantly inhibited the growth of 22RV1 cells
Proc Natl Acad Sci U S A. 2024 Oct 15;121(42):e2411321121.
C4-2B cells
7.5 µM
24 h
SR8278 significantly inhibited the growth of C4-2B cells
Proc Natl Acad Sci U S A. 2024 Oct 15;121(42):e2411321121.
mouse gingival fibroblasts (mGFs)
2.5 μM
To investigate whether BMAL1 regulates GSDMD-mediated pyroptosis through NR1D1, SR8278 treatment increased the protein levels of NLRP3 and CASPASE1 but decreased the expression and cleavage of GSDMD, significantly improving cell rupture and death
Int J Oral Sci. 2025 Feb 25;17(1):14.
BV-2 cells
10 μM, 20 μM
24 h
SR8278 increased Aβ internalization in a dose-dependent manner, with significant effects at 20 μM.
Aging Cell. 2020 Feb;19(2):e13078.
BV-2 cells
20 μM
24 h
SR8278, by inhibiting REV-ERBα/β activity, upregulated Bmal1 expression and accelerated microglial uptake of fAβ1-42 even when lysosomal degradation was blocked.
Aging Cell. 2020 Feb;19(2):e13078.
human primary keratinocytes
10 μM
24 h
SR8278 treatment significantly reduced HSV-1 antigen expression in the epidermis and decreased HSV-1 viral load.
JCI Insight. 2023 Oct 23;8(20):e171548.
HepG2 cells
10 μM
24 h
To evaluate the effect of SR8278 on the expression of REV-ERBα target genes G6Pase and PEPCK in HepG2 cells, results showed that SR8278 significantly increased the expression of these genes, presumably by blocking the action of the endogenous agonist heme.
ACS Chem Biol. 2011 Feb 18;6(2):131-4.
HEK293 cells
10 μM
24 h
To assess the REV-ERBα antagonist activity of SR8278 in HEK293 cells, results showed that SR8278 enhanced the expression of the reporter gene, presumably by blocking the action of the endogenous agonist heme.
ACS Chem Biol. 2011 Feb 18;6(2):131-4.
SR8278 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
GH3 xenograft tumor model
Intraperitoneal injection
50 mg/kg
Once daily for 10 days
SR8278 significantly inhibited the growth of GH3 xenograft tumors in mice, as evidenced by lower tumor volume and weight.
Theranostics. 2023 Apr 29;13(8):2657-2672
Mice
C4-2B xenograft tumor model
10 mg/kg
3 weeks
SR8278 significantly inhibited tumor growth
Proc Natl Acad Sci U S A. 2024 Oct 15;121(42):e2411321121.
Mice
Model of circadian rhythm disruption and periodontitis induced by simulated shift work
Intraperitoneal injection
500 μM(110 μL)
Every 2 days
To investigate whether SR8278 alleviates circadian disruption-aggravated periodontitis by increasing BMAL1 levels and reducing GSDMD-mediated pyroptosis. Results showed that SR8278 injection further increased BMAL1 levels, significantly reduced the N-terminal cleavage of GSDMD, and alleviated alveolar bone resorption and periodontal destruction
Int J Oral Sci. 2025 Feb 25;17(1):14.
Mice
Myeloid-specific Bmal1-deficient mice
Intraperitoneal injection
20 mg/kg
Single injection, monitored for 3 days
To investigate the effect of SR8278 on noncanonical inflammasome-mediated pyroptosis and lethality. The results showed that SR8278 significantly increased poly(I:C)-stimulated SAA1 transcription and noncanonical inflammasome-mediated lethality in mice.
Exp Mol Med. 2024 Feb;56(2):370-382
Mice
6-OHDA-lesioned Parkinson’s disease mouse model
Local injection into the midbrain VTA
20 µg/mouse
3 hours before each behavioral test, continuous behavioral testing
SR8278 exerted antidepressant and anxiolytic effects in 6-OHDA-lesioned mice, especially at dawn, restoring the circadian rhythm of mood-related behaviors.
Neurotherapeutics. 2022 Mar;19(2):592-607
Rats
Ischemia-reperfusion-induced acute lung injury model
Intraperitoneal injection
5 mg/kg
Single dose, lasting 30 minutes
SR8278 significantly blocked the protective effects of SR9009 against ischemia-reperfusion-induced lung injury
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