title: 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.
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53211, United States.
authors.forename: Premchendar
authors.initials: P
authors.lastname: Nandhikonda
authors.forename: Wen Z
authors.initials: WZ
authors.lastname: Lynt
authors.forename: Megan M
authors.initials: MM
authors.lastname: McCallum
authors.forename: Tahniyath
authors.initials: T
authors.lastname: Ara
authors.forename: Athena M
authors.initials: AM
authors.lastname: Baranowski
authors.forename: Nina Y
authors.initials: NY
authors.lastname: Yuan
authors.forename: Dana
authors.initials: D
authors.lastname: Pearson
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Bikle
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
authors.forename: Leggy A
authors.initials: LA
authors.lastname: Arnold
mesh_terms: D002460:Cell Line; D057166:High-Throughput Screening Assays; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008567:Membranes, Artificial; D008744:Methylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051958:Nuclear Receptor Coactivator 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D056921:Nuclear Receptor Coactivator 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D056918:Nuclear Receptor Coactivators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010539:Permeability; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D007211:Indoles; D008567:Membranes, Artificial; D008744:Methylamines; D051958:Nuclear Receptor Coactivator 2; D056918:Nuclear Receptor Coactivators; D018167:Receptors, Calcitriol; D050916:TRPV Cation Channels; C120776:TRPV6 channel; D056921:Nuclear Receptor Coactivator 3