The Development of VDR-coactivator Inhibitors and Their Evaluation Using Biochemical and Cell-based Assays
Date of Award
Master of Science
Nicholas Silvaggi, Xiaohua Peng
Antagonists, GW0742, PPARΔ, Steroid Receptor Coactivator-2, Vitamin D Receptor
The vitamin D receptor (VDR) belongs to the family of nuclear receptors and plays a crucial role in many biological processes such as cell differentiation, cell proliferation and calcium homeostasis. VDR is a good pharmaceutical target for many diseases including cancer, metabolic disorders, skin diseases and cardiovascular diseases. Upon binding with its endogenous ligand calcitriol in the body, VDR undergoes a conformational change that disrupts the interaction with corepressor proteins and instead enables the interaction with coactivator proteins that mediated transcription. The goal of the research is the development of new small molecules that will selectively inhibit the interaction between VDR and coregulators by binding to the ligand binding site of VDR.
Eleven VDR antagonists were synthesized based on GW0742 a potent PPARΔ agonist that inhibit VDR-mediated transcription at higher concentrations. The compounds were evaluated using cell-based and biochemical assays to determine their ability to inhibit the interaction between VDR and steroid receptor coactivator-2 (SRC-2) and to determine the ability to activate PPARΔ mediated transcription. BF040813F and BF090813A1 were the most active compounds towards VDR without activating PPARΔ. The simple accessibility of BF040813F, being a precursor compound, makes it an attractive candidate for further SAR studies.
Feleke, Belaynesh, "The Development of VDR-coactivator Inhibitors and Their Evaluation Using Biochemical and Cell-based Assays" (2014). Theses and Dissertations. 526.