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Discovery of the first irreversible small molecule inhibitors of the interaction between the vitamin D receptor and coactivators.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2012 May 24; Vol. 55 (10), pp. 4640-51. Date of Electronic Publication: 2012 May 16. - Publication Year :
- 2012
-
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.
- Subjects :
- Cell Line
High-Throughput Screening Assays
Humans
Indoles chemistry
Indoles pharmacology
Membranes, Artificial
Methylamines chemistry
Methylamines pharmacology
Nuclear Receptor Coactivator 2 antagonists & inhibitors
Nuclear Receptor Coactivator 2 metabolism
Nuclear Receptor Coactivator 3 antagonists & inhibitors
Nuclear Receptor Coactivator 3 metabolism
Nuclear Receptor Coactivators metabolism
Permeability
Protein Binding
Receptors, Calcitriol metabolism
Solubility
Structure-Activity Relationship
TRPV Cation Channels genetics
Transcription, Genetic drug effects
Indoles chemical synthesis
Methylamines chemical synthesis
Nuclear Receptor Coactivators antagonists & inhibitors
Receptors, Calcitriol antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 55
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22563729
- Full Text :
- https://doi.org/10.1021/jm300460c