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Discovery of the first irreversible small molecule inhibitors of the interaction between the vitamin D receptor and coactivators.


ABSTRACT: 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-corepressor binding and promote VDR-coactivator interactions. The interactions between VDR and coregulators are essential for VDR-mediated transcription. Small molecule inhibition of VDR-coregulator 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-coactivator inhibitors, 3-indolylmethanamines. Structure-activity 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-coactivator inhibitors with the ability to regulate the transcription of the human VDR target gene TRPV6.

SUBMITTER: Nandhikonda P 

PROVIDER: S-EPMC3364162 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Discovery of the first irreversible small molecule inhibitors of the interaction between the vitamin D receptor and coactivators.

Nandhikonda Premchendar P   Lynt Wen Z WZ   McCallum Megan M MM   Ara Tahniyath T   Baranowski Athena M AM   Yuan Nina Y NY   Pearson Dana D   Bikle Daniel D DD   Guy R Kiplin RK   Arnold Leggy A LA  

Journal of medicinal chemistry 20120516 10


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-corepressor binding and promote VDR-coactivator interactions. The interactions between VDR and coregulators are essential for VDR-mediated transcription. Small molecule inhibition of VDR-coregulator binding represents an alternative method to the traditional ligand-based appr  ...[more]

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