The peroxisome proliferator-activated receptors (PPARs) are ligand activated transcription factors belonging to the nuclear receptor superfamily and play key roles in multiple physiological pathway. Three PPAR receptor subtypes, designated as PPARα, PPARγ, and PPARδ, have been identified. PPARδ is recognized as a regulator of genes involved in fatty acid oxidation, reverse cholesterol transport, and carbon substrate utilization in skeletal muscle. GSK3787 is a potent and selective antagonist for PPARδ with pIC50 value of 6.6 in ligand displacement assay. GSK3787 completely antagonized the activity of PPARδ agonist 1 with a pIC50 of 6.9. GSK3787 was administered to human skeletal muscle cells at various doses and found to effectively antagonize the gene expression of CPT1a. This suggests that GSK3787 may selectively block the basal activity of the receptor on some PPARδ target genes highlighting the potential utility of this compound as a useful tool for further elucidating the biological role of PPARδ. GSK3787 was administered intravenously (0.5 mg/kg) and orally (10 mg/kg) to male C57BL/6 mice. Mean clearance (CL) and volume of distribution at steady state (Vss) following iv administration were 39 ± 11 (mL/min)/kg and 1.7 ± 0.4 L/kg, respectively. Following oral administration, good exposure (Cmax = 881 ± 166 ng/mL, AUCinf = 3343 ± 332 hng/mL), half-life (2.7 ± 1.1 h), and bioavailability (F = 77 ± 17%) were observed. Thus, GSK3787 has pharmacokinetic properties suitable for use as an in vivo PPARδ antagonist tool compound in mice[1].
作用机制
GSK3787 covalently modifies Cys249 within the ligand binding pocket[1].
GSK3787 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HCT116 cells
1 µM
24 hours
GSK3787 decreased c-Myc mRNA expression
Cancer Res. 2019 Mar 1;79(5):954-969.
SW620 cells
1 µM
24 hours
GSK3787 reduced active β-catenin levels
Cancer Res. 2019 Mar 1;79(5):954-969.
CT26 cells
1.0 µM
48 hours
GSK3787 blocked PPARD’s promotion of cell invasion
Cancer Res. 2019 Mar 1;79(5):954-969.
Rat pulmonary artery cells
1 µM
24 hours
GSK3787 alone had no significant effect on LPS-induced NO and IL-6 release in rat pulmonary artery, but co-incubation with GW0742 significantly reduced NO and IL-6 production.
Int J Mol Sci. 2021 Mar 19;22(6):3158.
AGS human gastric cancer cells
2 µg/mL
48 hours
To investigate the effect of PPARδ overexpression on CCL20 mRNA expression, results showed that PPARδ significantly upregulated CCL20 expression in AGS cells.
Gastric Cancer. 2023 Nov;26(6):904-917.
N87 human gastric cancer cells
2 µg/mL
48 hours
To investigate the effect of PPARδ overexpression on CCL20 mRNA expression, results showed that PPARδ significantly upregulated CCL20 expression in N87 cells.
Gastric Cancer. 2023 Nov;26(6):904-917.
Mouse gastric cancer cells
2 µg/mL
48 hours
To investigate the effect of PPARδ overexpression on CCL20 mRNA expression, results showed that PPARδ significantly upregulated CCL20 expression in mouse gastric cancer cells.
Gastric Cancer. 2023 Nov;26(6):904-917.
Porcine corpus luteum cells
25 µM
6 hours
To investigate the effect of GSK3787 on LPS-induced inflammation in porcine corpus luteum cells, the results showed that GSK3787 affected the expression of 88 differentially expressed genes.
Int J Mol Sci. 2023 Mar 5;24(5):4993.
GSK3787 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
ApcΔ580 mice
Oral
200 mg/kg
For 12 consecutive weeks
GSK3787 significantly reduced colonic tumor numbers and sizes
Cancer Res. 2019 Mar 1;79(5):954-969.
PpardTG mice
PpardTG mouse model
Oral
200 mg/kg
44 weeks
To investigate the inhibitory effect of GSK3787 on gastric cancer carcinogenesis in PpardTG mice, results showed that GSK3787 significantly suppressed the development and progression of gastric cancer.
Gastric Cancer. 2023 Nov;26(6):904-917.
Rats
Neonatal hypoxic-ischemic brain injury model
Intranasal administration
300 μg/kg
1 hour before HI and 24 hours post HI
GSK3787 significantly reversed the protective effects of GW0742, leading to increased infarct area and impaired neurological function
Neuropharmacology. 2018 Sep 15;140:150-161
Sprague-Dawley rats
Hypoxic-ischemic brain injury model
Intranasal administration
300 μg/kg
Administered 1 hour before HI and 24 hours post-HI
GSK3787 significantly increased NLRP3 expression, reversing the anti-inflammatory effects of GW0742 and leading to a significant increase in TNF-α expression.
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