Retinoid Receptors and Therapeutic Applications of RAR/RXR Modulators

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.

The molecular basis of the interactions between synthetic retinoic acid analogues and the retinoic acid receptors

“…47 Given this selectivity for RARβ, EC19 represents an excellent starting point for further structural optimisation. Few examples of RARβ-selective retinoids containing this metacarboxylate motif exist in the literature, 3,26 and given confirmed links between RARβ and the treatment of cancers (among other conditions), 4,[48][49][50] such a scaffold would be interesting to explore, particularly since the synthetic methodology associated with similar compounds is well understood. 9,21,51 Finally, as might be expected, the methyl ester of EC23 exhibited reduced binding affinity compared to the parent compound, particularly for RARγ (Table 3).…”

“…The presence of the methyl ester in EC19Me reduced the binding affinity for RARβ (but not 14 | J. Name., 2012, 00, [1][2][3] This journal is © The Royal Society of Chemistry 20xx…”

“…1,2 Due to this powerful and wide ranging biological activity, ATRA and its isomers have been used as therapeutics for the treatment of various cancers and skin conditions. 3,4 In addition, ATRA is routinely used in vitro as an inducer of cellular differentiation; however, its usage has limitations, as the compound readily isomerises to mixtures of ATRA, 9-cis-retinoic acid (9CRA), 13-cis-retinoic acid (13CRA) and other species. 5,6 This instability is derived from the five conjugated double bonds that absorb visible light at wavelengths of 300-400 nm.…”

“…Previous studies showed that EC23 induced neuronal differentiation in pluripotent stem cells at a lower Figure 1: Left, chemical structures of endogenous retinoids ATRA and 9CRA, synthetic retinoids EC23 and EC19, and synthetic retinoid esters EC23Me and EC19Me. 3,9 Right, proposed investigation into the interactions of natural and synthetic retinoids by combining in silico docking studies with an in vitro binding assay.…”

“…18,19 These divergent residues account for the observed selectivity of the different retinoic acids towards binding with RARα, β and γ, and have been exploited to inform the design of a variety of isotype-specific synthetic retinoids. 3,20,21 The second endogenous ligand for the RARs is 9CRA, a cisisomer of ATRA, which acts as an agonist for both RARs and a second class of retinoic acid receptor, the retinoid X-receptors, (RXR). [22][23][24] Crystallographic studies of the LBDs of both types of receptor show that although the overall architecture of RARs and RXRs is very similar, the shape of the ligand binding pocket differs markedly between RARs and RXRs.…”