Natural and Structure-based RXR Ligand Scaffolds and Their Functions
Angel R. de Lera.
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
Keywords: RXR, Heterodimers, Ligands, Rexinoids, Agonists, Antagonists, Natural Products, Rexinoid Scaffolds.
Rights & PermissionsPrintExport