Modulation of RXR function through ligand design

Pérez, Efrèn; Bourguet, William; Gronemeyer, Hinrich; Lera, Ángel R. de

doi:10.1016/j.bbalip.2011.04.003

Cited by 142 publications

(163 citation statements)

References 106 publications

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“…The major side effects associated with Bex include severe but reversible hypertriglyceridemia, central hypothyroidism, pancreatitis, and importantly hepatomegaly (83)(84)(85). In this study, only 1-week Bex treatment induced an increase in liver size up to 150%, a side effect that may have impacted CNS function, as measured by increased levels of soluble oA␤.…”

Section: E4fad-hpmentioning

confidence: 83%

Amyloid-β Pathology and APOE Genotype Modulate Retinoid X Receptor Agonist Activity in Vivo

Tai

Koster

Luo

et al. 2014

Journal of Biological Chemistry

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Background: Human APOE effects on RXR agonist activity are unclear. Results: In RXR agonist-treated EFAD mice, beneficial effects in APOE4 hippocampus include ABCA1/ABCG1-induced apoE lipoprotein association/lipidation. Detrimental effects in APOE3 and APOE4 cortex might be from systemic hepatomegaly. Conclusion: A␤ pathology and APOE genotype modulate RXR agonist effects. Significance: Although promising for later stage Alzheimer disease, detrimental side effects limit translational application of RXR agonists.

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Section: E4fad-hpmentioning

confidence: 83%

Amyloid-β Pathology and APOE Genotype Modulate Retinoid X Receptor Agonist Activity in Vivo

Tai

Koster

Luo

et al. 2014

Journal of Biological Chemistry

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“…These heterodimers have two distinct functions: First, they modulate the frequency of transcription initiation of target genes after binding to retinoic acid receptor response elements (RAREs) in their promoters; and second, they affect the efficiency of other signaling pathways ('crosstalk') [10]. RARs and RXRs form heterodimers, which are "non-permissive", that is unresponsive to RXR ligands on their own, but these agonists super activate transcription by synergizing with RAR ligands [21]. It is assumed that in these processes RAR heterodimerizes with RXR responding to RXR-selective ligands, which are inactive alone, strengthening by RAR-selective ligands [49].…”

Section: Therapeutic Applications Of Rar/rxr Heterodimer Modulators Imentioning

confidence: 99%

“…So, RXRα ligands (agonists and antagonists) have the potential to affect the signaling of numerous other pathways. Many recent reviews have described the mechanisms of RXRα as heterodimerization partners in various circumstances including development, metabolic diseases, and cancer [18][19][20][21][22][23][24][25]. Here we will discuss the latest insights into these various mechanisms how RXRα interacts with other nuclear receptors in cancer and other diseases in order to develop improved target-based drugs for cancer and other disease therapy.…”

Section: Introductionmentioning

confidence: 99%

The Function of Retinoid X Receptor α in Cancer Cells

Huang¹,

Chen²,

Shen³

2016

Biol syst Open Access

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The retinoid X receptor (RXR) is a member of the steroid/thyroid hormone superfamily of nuclear receptors (NRs) which are transcription factors that are essential in embryonic development, maintenance of differentiated phenotypes, metabolism and cell death. This review is to provide an overview of the mechanism of RXRα and RXRα signaling pathways involving RXR/TR3, RAR/RXR, PPAR/RXR, VDR/RXR, LXR/RXR, FXR/RXR in cancer cells and other diseases, which will enhance our ability to design rational therapeutic drugs for cancer. Recent studies have shown that an N-terminally truncated RXRα (tRXRα) exists in several cancer cell lines and primary tumors, which is considered as a kind of oncoprotein, demonstrating the new suitability of targeting tRXRα for cancer therapy.

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“…[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. 25 RARs possess a linear "I" shaped pocket, whereas the RXRs exhibit a shorter and more restrictive "L" shape. As a result, the linear retinoid ATRA mainly acts as a ligand for RARs while 9CRA exhibits high binding affinity for both the RARs and RXRs.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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. (2017) 'The molecular basis of the interactions between synthetic retinoic acid analogues and the retinoic acid receptors. ', MedChemComm., 8 (3). pp. 578-592. Further information on publisher's website:https://doi.org/10.1039/C6MD00680APublisher's copyright statement:Additional information: Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-pro t purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. All-trans-retinoic acid (ATRA) and its synthetic analogues EC23 and EC19 direct cellular differentiation by interacting as ligands for the retinoic acid receptor (RARα, β and γ) family of nuclear receptor proteins. To date, a number of crystal structures of natural and synthetic ligands complexed to their target proteins have been solved, providing molecular level snap-shots of ligand binding. However, a deeper understanding of receptor and ligand flexibility and conformational freedom is required to develop stable and effective ATRA analogues for clinical use. Therefore, we have used molecular modelling techniques to define RAR interactions with ATRA and two synthetic analogues, EC19 and EC23, and compared their predicted biochemical activities to experimental measurements of relative ligand affinity and recruitment of coactivator proteins. A comprehensive molecular docking approach that explored the conformational space of the ligands indicated that ATRA is able to bind the three RAR proteins in a number of conformations with one extended structure being favoured. In contrast the biologically-distinct isomer, 9-cis-retinoic acid (9CRA), showed significantly less conformational flexibility in the RAR binding pockets. These findings were used to inform docking studies of the synthetic retinoids EC23 and EC19, and their respective methyl esters. EC23 was found to be an excellent mimic for ATRA, and occupied similar binding modes to ATRA in all three target RAR proteins. In comparison, EC19 exhibited an alternative binding mode which reduces the strength of key polar interactions in RARα/γ but is well-suited to the larger RARβ binding pocket. In contrast, docking of the corresponding esters revealed the loss of key polar interactions which may explain the much reduced biological activity. Our computational results were complemented using an in vitro binding assay based on FRET measurements, which showed that EC23 was a strongly binding, pan-agonist of the RARs, while EC19 exhibited specificity for RARβ, as predicted by the docking studies. These findings can account for the distinct behaviour of EC23 and EC19 in cellular differentiation assays, and additionally, the methods described ...

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Modulation of RXR function through ligand design

Cited by 142 publications

References 106 publications

Amyloid-β Pathology and APOE Genotype Modulate Retinoid X Receptor Agonist Activity in Vivo

Amyloid-β Pathology and APOE Genotype Modulate Retinoid X Receptor Agonist Activity in Vivo

The Function of Retinoid X Receptor α in Cancer Cells

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

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