Home Metabolism PPAR antagonist GSK3787

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GSK3787 PPAR antagonist

GSK3787 is a selective and irreversible antagonist of PPARδ with pIC50 of 6.6, with no measurable affinity for hPPARα or hPPARγ.

GSK3787 PPAR antagonist Chemical Structure

Chemical Structure

Molecular Weight: 392.78

Purity & Quality Control

Related Products

Signaling Pathway

PPAR Signaling Pathways

PPAR Signaling Pathway

Mechanism of Action

Targets
PPARδ [1]
6.6(pIC50)

In vitro
In vitro

GSK3787 irreversibly antagonizes human and mouse PPARδ that covalently modifies Cys249 within the ligand binding pocket. This compound (1 μM) effectively antagonizes the agonist GW0742 stimulated transcription of CPT1a and PDK4 in human skeletal muscle cells, and effectively antagonize the basal gene expression of CPT1a. It shows no effective antiproliferative activity against colorectal cancer cells. [1]

This chemical (1 μM) completely antagonizes 50 nM GW0742-induced PPARβ/δ-dependent Angptl4 gene expression in wild-type fibroblasts and in keratinocytes. It (1 μM) largely antagonizes 50 nM GW0742-induced Angptl4 and Adrp mRNAs expression in skin cancer cell A341. This compound (1 μM) largely antagonizes GW0742-induced Angptl4 mRNAs expression in cancer cell lines MCF7 (breast), Huh7 (liver), and HepG2 (liver) cells but not in H1838 or A549 cells (lung). It (1 μM) largely antagonizes GW0742-induced increase of Adrp mRNA in Huh7 and HepG2 cells but not in H1838 cells. This chemical does not antagonize basal expression of either of these two PPARβ/δtarget genes in these cells. Neither GW0742 nor this compound has any effect on cell proliferation of these cells at concentrations ranging from 0.1 to 10 μM. It is able to modulate the association of both PPARβ/δ and PPARγ coregulator peptides in response to ligand activation. Efficacy of this chemical to modulate PPARγ activity is markedly lower than the efficacy of it to act as a PPARβ/δ antagonist. [2]
Kinase Assay Saturation binding assay
Using 96-well culture plates, 50 nM purified human PPARG LBD and the desired concentration of [3H]GW3738 are diluted to a total volume of 100 μL with buffer consisting of 50 mM KCl, 5 mM EDTA, 10 mM dithiothreitol (DTT), 50 mM HEPES, at pH 7. Saturation binding assays are conducted using concentrations of this compound ranging from 1 to 250 nM. Nonspecific binding at each concentration of [3H]GW3738 is estimated in parallel incubations containing 50 μM unlabeled GW 3738. Plates are incubated for 2 h at room temperature. Free ligand is separated from receptor-bound ligand by size exclusion chromatography using commercially available 96-well format spin columns. Samples (50 μL) from each well of a single test plate are loaded onto a buffer- and temperature-equilibrated 96-well gel filtration block. The block is placed on top of a clean microtiter plate and centrifuged at 1100 g for 4 min. Scintillation fluid (180 ul) is added to each well of the plate containing the eluent, and the plates are sealed and allowed to equilibrate for at least 4 h before counting in a counter. The amount of nonspecific binding at each concentration of [3H]GW3738 is subtracted from all wells and plots of this chemical concentration versus counts per minute (cpm) bound are constructed. The Kd values for [3H]GW3738 are determined from a nonlinear least squares fit of the data to a simple binding model.

In Vivo
In vivo

GSK3787 antagonizes ligand-induced PPARβ/δ-dependent gene expression in vivo. Oral administration of this compound has no effect on the expression of Angptl4 and Adrp mRNA in mouse colon epithelium. Coadministration of this chemical (10 mg/kg) effectively prevents the GW0742-induced expression of both Angptl4 and Adrp mRNA in wild-type mouse colon epithelium, which is correlated with reduced promoter occupancy of PPARβ/δ on the Angptl4 and Adrp genes. Administration of this compound had no effect on glucose tolerance. [2]

References
  • https://pubmed.ncbi.nlm.nih.gov/20128594/
  • https://pubmed.ncbi.nlm.nih.gov/20516370/
  • https://pubmed.ncbi.nlm.nih.gov/9427656/

Chemical Information

Molecular Weight 392.78 Formula

C15H12ClF3N2O3S
CAS No. 188591-46-0 SDF Download SDF
Synonyms N/A
Smiles C1=CC(=CC=C1C(=O)NCCS(=O)(=O)C2=NC=C(C=C2)C(F)(F)F)Cl

Storage and Stability

Storage (From the date of receipt)

In vitro
Batch:

DMSO : 79 mg/mL ( (201.13 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Water : Insoluble

Ethanol : Insoluble


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