Retinoid Receptors and Therapeutic Applications of RAR/RXR Modulators

Albane      le Maire; Susana      Alvarez; Pattabhiraman      Shankaranarayanan; Angel      R de Lera; William      Bourguet; Hinrich      Gronemeyer

doi:10.2174/156802612799436687

Abstract

Retinoic acid receptors (RARs) are ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate cell growth, differentiation, survival and death. Due to their regulatory potential, these nuclear receptors (NRs) are major drug targets for a variety of pathologies, including cancer and metabolic diseases. A large amount of RAR- and RXR-selective ligands, ranging from (partial) agonists to antagonists and inverse agonists, have been designed and the corresponding structural and functional analyses have provided deep insight into the molecular basis of ligand action. Ligands regulate, via allosteric conformational changes, the ability of these NRs to interact with different sets of coregulators, which in turn recruit enzymatically active complexes/machineries. Here, we describe strategies in the design of selective RXR and RAR modulators and review the structural mechanisms by which the diverse pharmacological classes of compounds modulate receptor functions. Finally, we discuss the perspectives for retinoid- and rexinoid-based therapies.

Keywords: Retinoic acid receptors, retinoid X receptors, agonists and antagonists action, ligand design, selective ligands, structure-function relationship, thee-dimensional structure, therapeutic potential, antagonists rexinoid apoptosis, retinoid- and rexinoid-based therapies