RXR-Specific Agonists and Modulators: A New Retinoid Pharmacology
Receptors for retinoic acid (RARs and RXRs), thyroid hormone (TRs), vitamin D (VDR), prostanoids (PPARs) and numerous orphan receptors for which ligands have not been identified play vital roles in vertebrate cell growth, development, differentiation, metabolism and homcostasis. These receptors, like most members of the nuclear hormone receptor superfamily, function as hormone-dependent transcription factors that regulate the expression of large gene networks. The important biological activities of nuclear hormone receptors combined with the ability to directly regulate their activity with small molecules has long made this superfamily of transcription factors a target for drug discovery. This review focuses on the retinoid X receptors (RXRs), first characterized as receptors for the vitamin A derivative 9-cis retinoic acid (for recent reviews see Mangelsdorf and Evans 1995; Mangelsdorf et al. 1995; Perlmann and Evans 1997). Recent work demonstrating that ligands for RXR may provide effective treatments for several types of cancers as well as for type II diabetes has lead to great interest in this class of nuclear hormone receptors that until recently were thought of as a “silent partner.”
KeywordsObesity Toxicity Leukemia Prostaglandin Tamoxifen
Unable to display preview. Download preview PDF.
- Gottardis MM, Bischoff ED, Shirley MA, Wagoner MA, Lamph WW, Heyman RA (1996) Chemoprevention of mammary carcinoma by LGD1069 (targretin): an RXR selective ligand. Cancer Res 15:5566–5570Google Scholar
- Hong H, Kulwant K, Garabedian M, Stallcup MR (1997) GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors. Mol Cell Biol 15:2735–2744Google Scholar
- Minucci S, Leid M, Toyama R, Saint-Jeannet J-P, Peterson VJ, Horn V, Ishmael JE, Bhat-tacharyya N, Dey A, Dawid IB, Ozato K (1997) Retinoid X receptor (RXR) within the RXR-retinoic acid receptor heterodimer binds its ligand and enhances retinoid-dependent gene expression. Mol Cell Biol 17:644–655PubMedGoogle Scholar
- Willson TM, Cobb JE, Cowan DJ, Wiethe RW, Correa ID, Prakash SR, Beck KD, Moore LB, Kliewer SA, Lehmann JM (1996) The structure-activity relationship between peroxisome-proliferator-activated receptor gamma and the antihyperglycemic activity of thiazolidinediones. J Med Chem 39:665–668PubMedCrossRefGoogle Scholar