Arnold Group at the University of Wisconsin Milwaukee-Research: Vitamin D Receptor

Vitamin D Receptor (VDR)

Arnold Group at the University of Wisconsin Milwaukee-Research: Vitamin D Transcription Suppression
VDR is a nuclear receptor which plays a critical role in cell differentiation, proliferation, and calcium homeostasis, and has been identified as an important pharmaceutical target for the treatment of metabolic disorders, skin diseases, cancer, autoimmune diseases, and cardiovascular diseases. VDR is a transcription factor, which is activated by binding to calcitriol (1,25-dihydroxyvitamin D3) and other active metabolites of vitamin D.
The corepressor are associated with the VDR-retinoid x receptor dimer in the absence of ligand, suppressing VDR-mediated transcription. Ligand binding permits VDR-coactivator interactions, and allows the formation of multi-protein complexes that activate VDR-mediated transcription.

 

Arnold Group at the University of Wisconsin Milwaukee-Research: VDR-coactivator interactions that activate VDR-mediated transcription

 

Arnold Group at the University of Wisconsin Milwaukee-Research: Vitamin D and the Expression of Genes
The expression of hundreds of genes are regulated by VDR in response to 1,25-dihydroxyvitamin D3. Our investigations are focused on genes directly regulated by VDR in order to understand the physiological role of VDR-coregulator interactions in VDR biology.

Vitamin D receptor-Coregulator Inhibitors

Arnold Group at the University of Wisconsin Milwaukee-Research: Small molecule inhibitors of the VDR-coactivator interaction

Arnold Group at the University of Wisconsin Milwaukee-Research: Small molecule inhibitors of the VDR-corepressor interaction

 

In order to modulate VDR-mediated transcription, we propose the development of small molecules to inhibit the interactions between VDR and coregulators (corepressor and coactivators).


We expect the inhibition of specific VDR-coregulator interactions will allow us to modulate the expression of specific genes.

 

  1. Small molecule inhibitors of the VDR-coactivator interaction: These molecules inhibit ligand-activated transcription.
  2. Small molecule inhibitors of the VDR-corepressor interaction: These molecules inhibit the repression of VDR target genes, and thus activate transcription.
The first irreversible inhibitor of the VDR-SRC2 interaction is based on a 3-indoylmethanamine structure (compound 31b). It selectively inhibit the interaction between VDR and coactivator peptide SRC2-3 among other nuclear receptor coactivator interactions tested. Confirmed was this inhibition by a pull-down western blot with VDR and SRC2. Importantly, we could show that these compounds inhibit the activation of transcription of the VDR target gene TRPV6 in the presence of calcitriol in DU145 prostate cancer cells. Currently, these compounds are investigated in cis-platinum restistant ovarian cancer cells.

 

First irreversible inhibitor of the VDR-SRC2 interaction