Peroxisome Proliferation-Activated Receptor 未 Agonist GW0742 Interacts Weakly with Multiple Nuclear Receptors, Including the Vitamin D Receptor

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• 作者：Premchendar Nandhikonda ; Adam Yasgar ; Athena M. Baranowski ; Preetpal S. Sidhu ; Megan M. McCallum ; Alan J. Pawlak ; Kelly Teske ; Belaynesh Feleke ; Nina Y. Yuan ; Chinedum Kevin ; Daniel D. Bikle ; Steven D. Ayers ; Paul Webb ; Ganesha Rai ; Anton Simeonov ; Ajit Jadhav ; David Maloney ; Leggy A. Arnold
• 刊名：Biochemistry
• 出版年：2013
• 出版时间：June 18, 2013
• 年：2013
• 卷：52
• 期：24
• 页码：4193-4203
• 全文大小：521K
• 年卷期：v.52,no.24(June 18, 2013)
• ISSN：1520-4995

文摘

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) 未 agonist GW0742 was among the identified VDR鈥揷oactivator inhibitors and has been characterized herein as a pan nuclear receptor antagonist at concentrations of >12.1 渭M. 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鈥揷oactivator 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.