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

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

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

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.

Original languageEnglish
Pages (from-to)4640-4651
Number of pages12
JournalJournal of Medicinal Chemistry
Volume55
Issue number10
DOIs
StatePublished - May 24 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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