生物活性

• 靶点	PPARγ IC50:3.3nM

• 描述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]

• 动物研究
  剂量	Mice: 5 mg/kg[4] (i.p.), 10 mg/kg[5] (i.p.)
  给药途径	i.p.

• 参考文献

• [1] Leesnitzer LM, Parks DJ, et al. Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662. Biochemistry. 2002 May 28;41(21):6640-50.

  [2] Bendixen AC, Shevde NK, et al. IL-4 inhibits osteoclast formation through a direct action on osteoclast precursors via peroxisome proliferator-activated receptor gamma 1. Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2443-8. Epub 2001 Feb 20.

  [3] Desmond JC, Mountford JC, et al. The aldo-keto reductase AKR1C3 is a novel suppressor of cell differentiation that provides a plausible target for the non-cyclooxygenase-dependent antineoplastic actions of nonsteroidal anti-inflammatory drugs. Cancer Res. 2003 Jan 15;63(2):505-12.