Referenced in: none

Automatically associated channels: TRP , TRPV , TRPV6

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

Authors: 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

Journal, date & volume: J. Med. Chem., 2012 May 24 , 55, 4640-51

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/22563729

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.