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lüll Discovery of the first irreversible small molecule inhibitors of the interaction between the vitamin D receptor and coactivators Nandhikonda P; Lynt WZ; McCallum MM; Ara T; Baranowski AM; Yuan NY; Pearson D; Bikle DD; Guy RK; Arnold LAJ Med Chem 2012[May]; 55 (10): 4640-51The 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.|Cell Line[MESH]|High-Throughput Screening Assays[MESH]|Humans[MESH]|Indoles/*chemical synthesis/chemistry/pharmacology[MESH]|Membranes, Artificial[MESH]|Methylamines/*chemical synthesis/chemistry/pharmacology[MESH]|Nuclear Receptor Coactivator 2/antagonists & inhibitors/metabolism[MESH]|Nuclear Receptor Coactivator 3/antagonists & inhibitors/metabolism[MESH]|Nuclear Receptor Coactivators/*antagonists & inhibitors/metabolism[MESH]|Permeability[MESH]|Protein Binding[MESH]|Receptors, Calcitriol/*antagonists & inhibitors/metabolism[MESH]|Solubility[MESH]|Structure-Activity Relationship[MESH]|TRPV Cation Channels/genetics[MESH]|Transcription, Genetic/drug effects[MESH] |