GW9662 is a selective and irreversible PPARγ antagonist with IC50 value of 5.4nM, 10- and 600-fold selectivity against PPARα and PPARδ with IC50 values of 39nM and 1.2μM, respectively. GW9662 had no effect on the ability of any of the PPARs to form heterodimers with RXR. GW9662 could dose-dependently antagonize PPARγ-GAL4-mediated transcription induced by rosiglitazone with IC50 value of 7.6nM. Consistent with this, rosiglitazone-induced increases in aP2 and Oil Red O staining could be completely blocked in C3H10T1/2 cells treated with 1μM GW9662, suggesting the anti-adipogenesis function of GW9662[1]. GW9662 within 2μM clearly blocked the ability of IL-4 (0.1, 0.5ng/ml, but not 1ng/ml) to suppress RANKL/M-CSF-induced osteoclastogenesis in bone marrow monocytes through inhibition of PPARγ1[2]. GW 9662 at concentration of 1μM could antagonize the potentiation of HL-60 cell differentiation induced by PGD2, PGJ2, indomethacin and MPA post 4 days[3].
作用机制
GW9662 exhibited a competition binding assay against the human ligand binding domain and covalently modified Cys of PPARγ.[1]
GW9662 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Human T cells
10 µM
4 days
To evaluate the effect of GW9662 on the differentiation of human T cells into regulatory T cells (Tregs), results showed that GW9662 inhibited Treg differentiation.
Cell Mol Immunol. 2023 Jun;20(6):666-679.
CGNPs
50 nM and 100 nM
24 h
GW9662 treatment resulted in a significant reduction of PPARγ, accompanied by decreased levels of HKII, PKM2, and Glut4, indicating that PPARγ activity is required for glycolysis and ongoing cell division
Acta Neuropathol. 2012 Apr;123(4):587-600.
human mesenchymal stem cells (hMSCs)
10 μM
8 days
Enhancing Wnt signaling and osteogenesis in hMSCs by inhibiting PPARγ
Spine J. 2017 Mar;17(3):418-430.
GW9662 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
CTCF-deficient mice
Injection
100 μM
Daily for 2 weeks
Inhibition of PPARγ by GW9662 significantly reduced the expression of CD36 and lipid accumulation in the livers of CTCF-deficient mice
1.5, 15 or 150 nmoles (topical) or 1 or 5 mg/kg (ip)
24 hours or 72 hours
GW9662 treatment resulted in increased UVB-induced apoptosis and inflammation
Int J Cancer. 2012 Oct 1;131(7):E1055-66
Mice
C57BL/6 mice
Intragastric administration
5 mg/kg
Once daily for 3 days
GW9662 significantly increased the overall number of E. coli recovered from the colon of mice and drove a nitrate respiration-dependent E. coli expansion.
Science. 2017 Aug 11;357(6351):570-575
Mice
Experimental autoimmune encephalomyelitis (EAE) model
Intraperitoneal injection
2 mg/kg
Daily for 28 days
To evaluate the effect of GW9662 on disease severity in the EAE model, results showed that GW9662 reduced EAE disease severity and decreased the frequency of peripheral Tregs.
Cell Mol Immunol. 2023 Jun;20(6):666-679.
Mice
Hepatic ischemia/reperfusion injury model
Intraperitoneal injection
1.0mg/kg
Single injection, lasting 30 minutes
GW9662 was used to block PPAR γ activity, and the results showed that the protective effect of 15d-PGJ2 against hepatic ischemia/reperfusion injury is not dependent on PPAR γ.
Ann Surg. 2014 Jul;260(1):118-27
Mice
NeuroD2-SmoA1 mice
Intraperitoneal injection
10 mg/kg
Once daily for 8 days
GW9662 treatment significantly reduced levels of glycolytic markers and cyclin D2, and extended the survival of medulloblastoma-bearing mice
Acta Neuropathol. 2012 Apr;123(4):587-600.
Mice
Intracerebral hemorrhage model
Intraperitoneal injection
5 mg/kg
Once daily until euthanasia
GW9662 treatment decreased rosiglitazone-induced expression of alternative activation markers (especially IL-10) and abolished PPAR γ-mediated hematoma resolution.
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