Peroxisome proliferation-activated receptor δ agonist GW0742 interacts weakly with multiple nuclear receptors, including the vitamin D receptor.

Methods Development
Therapeutic Approaches


A high-throughput screening campaign was conducted to identify small molecules with the ability to inhibit the interaction between the vitamin D receptor (VDR) and steroid receptor coactivator 2. These inhibitors represent novel molecular probes for modulating gene regulation mediated by VDR. Peroxisome proliferator-activated receptor (PPAR) δ agonist GW0742 was among the identified VDR-coactivator inhibitors and has been characterized herein as a pan nuclear receptor antagonist at concentrations of > 12.1 μM. The highest antagonist activity for GW0742 was found for VDR and the androgen receptor. Surprisingly, GW0742 behaved as a PPAR agonist and antagonist, activating transcription at lower concentrations and inhibiting this effect at higher concentrations. A unique spectroscopic property of GW0742 was identified as well. In the presence of rhodamine-derived molecules, GW0742 increased the fluorescence intensity and level of fluorescence polarization at an excitation wavelength of 595 nm and an emission wavelength of 615 nm in a dose-dependent manner. The GW0742-inhibited NR-coactivator binding resulted in a reduced level of expression of five different NR target genes in LNCaP cells in the presence of agonist. Especially VDR target genes CYP24A1, IGFBP-3, and TRPV6 were negatively regulated by GW0742. GW0742 is the first VDR ligand inhibitor lacking the secosteroid structure of VDR ligand antagonists. Nevertheless, the VDR-meditated downstream process of cell differentiation was antagonized by GW0742 in HL-60 cells that were pretreated with the endogenous VDR agonist 1,25-dihydroxyvitamin D3.


Nandhikonda, Premchendar; Yasgar, Adam; Baranowski, Athena M; Sidhu, Preetpal S; McCallum, Megan M; Pawlak, Alan J; Teske, Kelly; Feleke, Belaynesh; Yuan, Nina Y; Kevin, Chinedum; Bikle, Daniel D; Ayers, Steven D; Webb, Paul; Rai Bantukallu, Ganesha; Simeonov, Anton; Jadhav, Ajit; Maloney, David; Arnold, Leggy A;


  • Cell Line, Tumor
  • Cell Nucleus/ metabolism
  • DNA/ chemistry
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • HL-60 Cells
  • Humans
  • Inhibitory Concentration 50
  • Ligands
  • Nuclear Receptor Coactivator 2/ chemistry
  • PPAR delta/ agonists
  • Protein Binding
  • Receptors, Calcitriol/ chemistry
  • Rhodamines/ chemistry
  • Spectrophotometry/ methods
  • Thiazoles/ pharmacology

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