The proliferator-activated receptor β/δ (PPARβ/δ) is a fatty acid-regulated nuclear receptor implicated as a key regulator of fatty acid utilization, glucose disposal, and inflammation. In addition, PPARβ/δ signaling has been implicated in regulating cell proliferation and angiogenesis. Therefore, PPARβ/δ is a promising target for the discovery of medicines for metabolic diseases. GSK0660 is a potent antagonist of PPARβ/δ with a pIC50 of 6.8 (∼160 nM) and is nearly inactive on PPARα and PPARγ with IC50s above approximately 10 μM. The effect of GSK0660 on the expression of PPARβ/δ target genes in skeletal muscle cells was determined. GSK0660 reduced CPT1a expression below the basal vehicle-treated level by approximately 50% at 100 nM. Titration of the fluorescein-labeled PPARβ/δ LBD (ligand binding domain) with GSK0660 resulted in a dose-dependent increase in the observed anisotropy. This clearly demonstrated that GSK0660 induces a different conformation of helix 12 than observed with the PPARβ/δ agonists. GSK0660 reduced the association between the PPARβ/δ LBD and the LxxLL peptide, whereas the interaction with the CoRNR box peptide was increased. This activity was consistent with GSK0660 acting as an antagonist of the PPARβ/δ. Primary human skeletal muscle cells were treated with 1000 nM GSK0660 for 16 h. GSK0660 may strengthen corepressor interactions with the peroxisome proliferators response element (PPRE) containing regulatory regions of the CPT1a and ANGPTL4 genes to inhibit their expression[2]. GSK0660 significantly reduced serum-induced HRMEC proliferation and tube formation in a dose-dependent manner. Both intravitreal injection and intraperitoneal injection of GSK0660 significantly reduced retinal NV (neovascularization)[3].
作用机制
GSK0660 exhibits potently binding on the PPARβ/δ ligand binding domain (LBD)[2].
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