Discovery of the first irreversible small molecule inhibitors of the interaction between the vitamin D receptor and coactivators.
Basic Information
ID: ALA2069300
Journal: J Med Chem
Title: Discovery of the first irreversible small molecule inhibitors of the interaction between the vitamin D receptor and coactivators.
Authors: Nandhikonda P, Lynt WZ, McCallum MM, Ara T, Baranowski AM, Yuan NY, Pearson D, Bikle DD, Guy RK, Arnold LA.
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.
CiteXplore: 22563729
DOI: 10.1021/jm300460c
Patent ID: ┄