Cell lines

Fibroblasts, keratinocytes, skin cancer cell A341, cancer cell lines MCF7 (breast), Huh7 (liver), and HepG2 (liver) cells, Huh7, HepG2 cells

Preparation method

The solubility of this compound in DMSO is >15.8 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

0.1-1.0 μM, 24 h

Applications

GSK3787 (1 μM) completely antagonized 50 nM GW0742-induced PPARβ/δ-dependent Angptl4 gene expression in wild-type fibroblasts and in keratinocytes. GSK3787 (1 μM) largely antagonized 50 nM GW0742-induced Angptl4 and Adrp mRNAs expression in skin cancer cell A341. GSK3787 (1 μM) largely antagonized GW0742-induced Angptl4 mRNAs expression in cancer cell lines MCF7 (breast), Huh7 (liver), and HepG2 (liver) cells. GSK3787 (1 μM) largely antagonizesd GW0742-induced increase of Adrp mRNA in Huh7 and HepG2 cells.

Animal models

male wild-type and Pparβ/δ-null mice

Dosage form

10 mg/kg, oral gavage 3 h before euthanasia

Application

Administration of GSK3787 (10 mg/kg) effectively prevented the GW0742-induced expression of both Angptl4 and Adrp mRNA in wild-type mouse colon epithelium, which was correlated with reduced promoter occupancy of PPARβ/δ on the Angptl4 and Adrp genes. Administration of GSK3787 showed no effect on glucose tolerance.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

GSK3787 is a novel and irreversible antagonist of the peroxisome proliferator-activated receptor-β/δ (PPAR-β/δ) that covalently binds to a cysteine residue in the ligand-binding domain of PPAR- β/δ. Although it responses to ligand activation to modulate the association of both PPAR-β/δ and PPAR-γ coregulator peptides, GSK3787 exhibits considerably higher antagonism of PPAR-β/δ than that of PPAR-γ. Results of recent studies have shown that oral administration of GSK3787 results in the antagonism of GW0742-induced overexpression of Angptl4 and Adrp mRNA in wild-type mouse colon, which is correlated with reduced promoter occupancy of PPAR-β/δ on the Angptl4 and Adrp genes.

Reference

[1].Palkar PS, Borland MG, Naruhn S, Ferry CH, Lee C, Sk UH, Sharma AK, Amin S, Murray IA, Anderson CR, Perdew GH, Gonzalez FJ, Müller R, Peters JM. Cellular and pharmacological selectivity of the peroxisome proliferator-activated receptor-beta/delta antagonist GSK3787. Mol Pharmacol. 2010;78(3):419-430