Modulating vitamin D receptor–coregulator binding with small molecules

Nuclear receptor coregulators (coactivators and corepressors) play essential roles in nuclear receptor–mediated transcription. Depending on their amino acid sequence, they can bind the vitamin D receptor (VDR) in the presence or absence of ligand and enable activation or repression of gene transcription. Coregulators interact with nuclear receptors and certain other transcription factors, which impedes the characterization of their function during VDR-mediated transcription. This chapter summarizes recent experimental efforts to develop coactivator-binding inhibitors (CBIs) that selectively bind VDR and disrupt the interaction with coregulators. Following the discovery of peptide-based VDR CBIs, peptidomimetics including cyclic peptides and peptides bearing unnatural amino acids resulted in VDR CBIs with cellular activity. Crystal structures of coactivator peptides bound to VDR have enabled the rational design of novel small molecule–based VDR CBIs. In parallel, high throughput screening identified irreversible VDR CBIs with anticancer properties. Currently, most of these inhibitors have been developed for estrogen and androgen receptors because of their antitumor properties. In the future, it is expected that lessons learned from androgen receptor and estrogen receptor CBIs can be applied to the development of novel VDR CBIs. The use of these inhibitors as molecular probes is expected to further our understanding of the specific functions of VDR–coregulator interactions during VDR-mediated transcription.