Discovery of the First Irreversible Small Molecule Inhibitors of the Interaction between the Vitamin D Receptor and Coactivators

作者：Nandhikonda Premchendar; Lynt Wen Z; McCallum Megan M; Ara Tahniyath; Baranowski Athena M; Yuan Nina Y; Pearson Dana; Bikle Daniel D; Guy R Kiplin; Arnold Leggy A^*

来源：Journal of Medicinal Chemistry, 2012, 55(10): 4640-4651.

DOI：10.1021/jm300460c

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.

• 出版日期2012-5-24