The vitamin D receptor (VDR) belongs to the superfamily of nuclear receptors and is activated by the endogenous ligand 1,25-dihydroxyvitamin D3. The genomic effects mediated by VDR consist of the activation and repression of gene transcription, which includes the formation of multiprotein complexes with coregulator proteins. Coregulators bind many nuclear receptors and can be categorized according to their role as coactivators (gene activation) or corepressors (gene repression). Herein, different approaches to develop compounds that modulate the interaction between VDR and coregulators are summarized. This includes coregulator peptides that were identified by creating phage display libraries. Subsequent modification of these peptides including the introduction of a tether or nonhydrolyzable bonds resulted in the first direct VDR-coregulator inhibitors. Later, small molecules that inhibit VDR-coregulator inhibitors were identified using rational drug design and high-throughput screening. Early on, allosteric inhibition of VDR-coregulator interactions was achieved with VDR antagonists that change the conformation of VDR and modulate the interactions with coregulators. A detailed discussion of their dual agonist/antagonist effects is given as well as a summary of their biological effects in cell-based assays and in vivo studies.
Keywords: Coactivator; Coregulator; Coregulator peptides; Corepressor; VDR; VDR antagonist; VDR–coregulator inhibitor; Vitamin D receptor.
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