T0070907

The peroxisome proliferator-activated receptor-γ (PPARγ) is the nuclear receptor responsible for transducing the therapeutic activity of the thiazolidinediones (TZDs). TZDs are a group of structurally related synthetic PPARγ receptor agonists with antidiabetic actions in vivo.^1,2 There are many PPARγ agonists, including 15-deoxy-Δ^12,14-prostaglandin J₂ and azelaoyl PAF, which are naturally derived.^3,4 However, only a few antagonists have been reported.⁵ T0070907 is a potent and selective antagonist of the human PPARγ with an apparent IC₅₀ of 1 nM for the binding inhibition of rosiglitazone, a reference TZD. T0070907 covalently binds to Cys³¹³ of PPARγ, inducing conformational changes that block the recruitment of transcriptional cofactors to the PPARγ/RXR heterodimer.⁶

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1. Willson, T.M., Cobb, J.E., Cowan, D.J., et al. The structure-activity relationship between peroxisome proliferator-activated receptor γ agonism and the antihyperglycemic activity of thiazolidinediones. J. Med. Chem. 39(3), 665-668 (1996).

2. Cantello, B.C.C., Cawthorne, M.A., Cottam, G.P., et al. [[ω-(Heterocyclylamino)alkoxy]benzyl]-2,4-thiazolidinediones as potent antihyperglycemic agents. J. Med. Chem. 37, 3977-3985 (1994).

3. Davies, S.S., Pontsler, A.V., Marathe, G.K., et al. Oxidized alkyl phospholipids are specific, high affinity peroxisome proliferator-activated receptor γ ligands and agonists. The Journal of Biological Chemisty 276(19), 16015-16023 (2001).

4. Maxey, K.M., Hessler, E., MacDonald, J., et al. The nature and composition of 15-deoxy-Δ12,14-PGJ₂. Prostaglandins Other Lipid Mediat. 62(1), 15-21 (2000).

5. Wright, H.M., Clish, C.B., Mikami, T., et al. A synthetic antagonist for the peroxisome proliferator-activated receptor γ inhibits adipocyte differentiation. The Journal of Biological Chemisty 275(3), 1873-1877 (2000).

6. Lee, G., Elwood, F., McNally, J., et al. T0070907, a selective ligand for peroxisome proliferator-activated receptor γ, functions as an antagonist of biochemical and cellular activities. The Journal of Biological Chemisty 277(22), 19649-19657 (2002).

Díaz-Alonso, J., Paraíso-Luna, J., Navarrete, C., et al. VCE-003.2, a novel cannabigerol derivative, enhances neuronal progenitor cell survival and alleviates symptomatology in murine models of Huntington’s disease. Sci. Rep. 6, 29789 (2016).

Malaviya, A., and Sylvester, P.W. Synergistic antiproliferative effects of combined g-tocotrienol and PPARg antagonist treatment are mediated through PPARg-independent mechanisms in breast cancer cells. PPAR Res. 2014(439146), (2014).