Nuclear receptor drug discovery

Nuclear receptors (NR) are ligand-activated transcription factors that regulate the activation of a variety of important target genes. There are 48 genes that encode NRs in the human genome, and these receptors now represent one of the most important targets for therapeutic drug development. Successful identification of selective NR modulators has transformed the NR drug discovery strategy from the designing of synthetic compounds that mimic the full function of cognate ligands to developing compounds that selectively modulate the functional activity of an NR in a manner that is distinct from the cognate ligands. Current efforts regarding NR drug development continue to focus on improving the function and tissue selectivity of drug candidates to reduce undesirable side effects. This review focuses on modulators of the glucocorticoid receptor (GR), androgen receptor (AR), and pregnane X receptor (PXR).