Conformational Effects on Retinoid Receptor Selectivity. 2. Effects of Retinoid Bridging Group on Retinoid X Receptor Activity and Selectivity

Abstract

The natural retinoid 9-cis-retinoic acid is an activating ligand for both the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are members of the retinoid/thyroid hormone/steroid hormone family of nuclear receptor proteins that activate gene transcription through specific response elements. The pharmacophoric groups necessary to confer RXR selectivity were established by evaluating the ability of 21 conformationally restricted retinoids to activate the TREpal retinoic acid receptor response element for gene transcription in the presence of one of the three RAR subtypes or RXR alpha. In contrast to those retinoids selective for the RARs, these RXR-selective retinoids have one less atom in the bridge linking the hydrophobic and carboxylic acid termini of the retinoid skeleton. Therefore, a one-carbon bridge replaces the 19-methyl group and 9E-double bond of 9-cis-retinoic acid and is further functionalized by inclusion in an isopropylidene group, a dioxolane ring, or a cyclopropane ring for optimal RXR alpha activity and selectivity. In addition, the beta-geranylidene and 20-methyl-(11E,13E)-dienoic acid groups of 9-cis-retinoic acid are replaced by a 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl ring and a 4-carboxylphenyl ring, respectively, for optimal activation and selectivity. RXR alpha selectivity is reduced on replacement of the 4-carboxylphenyl group by a 2-carboxyl-5-thienyl group or the 9-cis-retinoic acid methylpentadienoic acid terminus.

Metabolism to a response pathway selective retinoid ligand during axial pattern formation

“…We investigated whether 9-cis-4-oxo-RA is a non-RXR agonist in RAR-RXR heterodimers, using the RXR-specific agonist SR11246 (36). Similarly as reported in investigations in cell lines (10)(11)(12), SR 11246 alone failed to cause significant activation of a DR-5 RA response element containing reporter via endogenous RARs and RXRs in early Xenopus embryos, but caused synergistic activation when combined with RAR-specific ligands [RA, 4-oxo-RA, or the RAR␣-specific (at suboptimal concentrations) ligand Am80] (Fig.…”

Defining the Communication between Agonist and Coactivator Binding in the Retinoid X Receptor α Ligand Binding Domain

“…We have demonstrated that 9cUAB30 compared well with Targretin in its capacity to prevent mammary cancer (21)(22)(23)(24)(25). The in vitro studies presented here also show how similar each rexinoid is in blocking ErbB2-oncogenic transformation, consistent with in vivo studies.…”

“…Although 9cUAB30 is slightly less potent than Targretin or 9cRA, it displays a higher degree of RXR selectivity. 9cUAB30 has also been shown to be effective in cancer prevention models (21)(22)(23)(24)(25). 9cUAB30 is a tissue-selective RXR agonist; it does not act as an agonist in liver to activate lipid biosynthesis although it has agonist capabilities in cancer cells (26).…”

Classical and novel retinoids: their targets in cancer therapy

“…RAR␣, ␤ and ␥ as well as RXR selective retinoids have been reported by a number of groups. 19,[25][26][27][28][29][30][31] These retinoids display selectivity in terms of their binding and transactivation of the retinoid receptor classes and subclasses. The advantages of these receptor selective retinoids, when compared to the natural retinoids, include their enhanced stability, reduced toxicity and activity in cells which display resistance to RA and 9-cis-RA.…”