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Orphan nuclear receptors, PXR and LXR: new ligands and therapeutic potential

Found in almost all animal species, orphan nuclear receptors (NRs) represent a unique and pivotal resource to uncover new regulatory systems that impact on both health and human diseases. Some of the current marketed drugs are known to target orphan NRs. Examples include the anticancer and retinoic X receptor (RXR)-targeting bexarotene (Targretin®, Ligand Pharmaceuticals, Inc.) and the antidiabetic and peroxisome proliferator-activated receptor (PPAR)-γ-targeting thiaozolidinediones. Several studies presented at a recent conference (Orphan and Nuclear Receptors – New Therapeutic Developments) have provided new insights into several orphan NRs, including the pregnane X receptor (PXR), the liver X receptor (LXR), the constitutive androstane receptor (CAR), PPAR and the RXR. This paper will focus on PXR and LXR, whose recent target gene analysis and ligand identification have raised both promises and practical concerns as to whether or not these receptors can be used as therapeutic targets.