title: Peroxisome proliferation-activated receptor δ agonist GW0742 interacts weakly with multiple nuclear receptors, including the vitamin D receptor.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, USA.
authors.forename: Premchendar
authors.initials: P
authors.lastname: Nandhikonda
authors.forename: Adam
authors.initials: A
authors.lastname: Yasgar
authors.forename: Athena M
authors.initials: AM
authors.lastname: Baranowski
authors.forename: Preetpal S
authors.initials: PS
authors.lastname: Sidhu
authors.forename: Megan M
authors.initials: MM
authors.lastname: McCallum
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Pawlak
authors.forename: Kelly
authors.initials: K
authors.lastname: Teske
authors.forename: Belaynesh
authors.initials: B
authors.lastname: Feleke
authors.forename: Nina Y
authors.initials: NY
authors.lastname: Yuan
authors.forename: Chinedum
authors.initials: C
authors.lastname: Kevin
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Bikle
authors.forename: Steven D
authors.initials: SD
authors.lastname: Ayers
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.forename: Ganesha
authors.initials: G
authors.lastname: Rai
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.forename: David
authors.initials: D
authors.lastname: Maloney
authors.forename: Leggy A
authors.initials: LA
authors.lastname: Arnold
mesh_terms: D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D004247:DNA / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D051958:Nuclear Receptor Coactivator 2 / Q000737:chemistry*; D047494:PPAR delta / Q000819:agonists*; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000737:chemistry*; D012235:Rhodamines / Q000737:chemistry; D013053:Spectrophotometry / Q000379:methods; D013844:Thiazoles / Q000494:pharmacology*; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D004247:DNA; D008024:Ligands; D051958:Nuclear Receptor Coactivator 2; D047494:PPAR delta; D018167:Receptors, Calcitriol; D012235:Rhodamines; D013844:Thiazoles; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds