Discovery of the First Irreversible Small Molecule Inhibitors of the Interaction between the Vitamin D Receptor and Coactivators

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• 作者：Premchendar Nandhikonda ; Wen Z. Lynt ; Megan M. McCallum ; Tahniyath Ara ; Athena M. Baranowski ; Nina Y. Yuan ; Dana Pearson ; Daniel D. Bikle ; R. Kiplin Guy ; Leggy A. Arnold
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 24, 2012
• 年：2012
• 卷：55
• 期：10
• 页码：4640-4651
• 全文大小：425K
• 年卷期：v.55,no.10(May 24, 2012)
• ISSN：1520-4804

文摘

The vitamin D receptor (VDR) is a nuclear hormone receptor that regulates cell proliferation, cell differentiation, and calcium homeostasis. The receptor is activated by vitamin D analogues that induce the disruption of VDR鈥揷orepressor binding and promote VDR鈥揷oactivator interactions. The interactions between VDR and coregulators are essential for VDR-mediated transcription. Small molecule inhibition of VDR鈥揷oregulator binding represents an alternative method to the traditional ligand-based approach in order to modulate the expression of VDR target genes. A high throughput fluorescence polarization screen that quantifies the inhibition of binding between VDR and a fluorescently labeled steroid receptor coactivator 2 peptide was applied to discover the new small molecule VDR鈥揷oactivator inhibitors, 3-indolylmethanamines. Structure鈥揳ctivity relationship studies with 3-indolylmethanamine analogues were used to determine their mode of VDR-binding and to produce the first VDR-selective and irreversible VDR鈥揷oactivator inhibitors with the ability to regulate the transcription of the human VDR target gene TRPV6.