Natural and Structure-based RXR Ligand Scaffolds and Their Functions

Retinoid X receptors (RXRs) are promiscuous partners of heterodimeric associations with other members of the Nuclear Receptor (NR) superfamily. Through these liaisons RXR ligands (“rexinoids”) either transcriptionally activate on their own the “permissive” subclass of heterodimers (PPAR/RXR, LXR/RXR, FXR/RXR) or synergize with partner ligands in the “non-permissive” subclass of heterodimers (RAR/RXR, VDR/RXR and TR/RXR). The nature and extent of the interaction of the ligand-receptor complexes with co-regulators, which is cell and context-dependent, results ultimately in transcriptional modulation of cognate gene networks. RXR modulators hold therapeutical potential for the treatment of cancer and other diseases related to nutrient acquisition and disposal, among them metabolic diseases. A rexinoid (bexarotene) has indeed reached the clinic for the treatment of cutaneous T-cell lymphoma. The modulation of RXR function by rexinoids acting as agonists, parcial agonists, inverse agonists or antagonists is encoded in the structure of the ligandreceptor complexes. A very large number of rexinoids with a wide structural diversity has been published. In addition to natural products and other ligands discovered by HTS or mere serendipity, most rexinoids have been rationally designed based on the structures of existing complexes with RXR determined by X-Ray or based on Molecular Modeling. Although the structural rationale for the modulation of the ligand-receptor complexes is reasonably well understood, it has not yet been possible to predict the correlation between ligand structure and physiological response, particularly in the case of heterodimer-selective rexinoids.