Noncanonical mechanisms to regulate nuclear receptor signaling.

Nuclear receptor (NR)-targeted therapies comprise a large class of clinically employed drugs. A number of drugs currently being used against this protein class were designed as structural analogs of the endogenous ligand of these receptors. In recent years, there has been significant interest in developing newer strategies to target NRs, especially those that rely on mechanistic pathways of NR function. Prominent among these are noncanonical means of targeting NRs, which include selective NR modulation, NR coactivator interaction inhibition, inhibition of NR DNA binding, modulation of NR cellular localization, modulation of NR ligand biosynthesis and downregulation of NR levels in target tissues. This article reviews each of these promising emerging strategies for NR drug development and highlights some of most significant successes achieved in using them.