Ligand Design for Modulation of RXR Functions

Abstract

Retinoid X receptors (RXRs) are promiscuous partners of heterodimeric associations with other members of the Nuclear Receptor (NR) superfamily. RXR ligands (“rexinoids”) either transcriptionally activate the “permissive” subclass of heterodimers or synergize with partner ligands in the “nonpermissive” subclass of heterodimers. The rationale for rexinoid design with a wide structural diversity going from the structures of existing complexes with RXR determined by X-Ray, to natural products and other ligands discovered by high-throughput screening (HTS), mere serendipity, and rationally designed based on Molecular Modeling, will be described. Included is the new generation of ligands that modulate the structure of specific receptor surfaces that serve to communicate with other regulators. The panel of the known RXR agonists, partial (ant)agonists, and/or heterodimer-selective rexinoids require the exploration of their therapeutic potential in order to overcome some of the current limitations of rexinoids in therapy.