Identification of a New RXRα Antagonist Targeting the Coregulator-Binding Site

Chen, Fan; Liu, Jie; Huang, Ming‐Feng; Hu, Mengjie; Su, Ying; Zhang, Xiaokun

doi:10.1021/ml5000405

Cited by 30 publications

(23 citation statements)

References 26 publications

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“…Recently, by employing a docking-based virtual screening approach, we identified some small molecules that bind to the coregulator-binding surface of RXRα, a region where the binding sites of the corepressor and the coactivator overlap ( Figure 4A). One of the identified binders, 23, can regulate the biological functions of tRXRα, including inhibition of TNFα-induced interaction of tRXRα with p85α, inhibition of AKT activation in vitro and in animals, and induction of apoptosis [56] . Compound 23 doesn't bind to the LBP and represents the first example of an RXRα modulator that acts via the coregulator-binding site rather than the classical ligandbinding pocket.…”

Section: Novel Surface Binding Sites Of Rxrα As Alternate Sites For Tmentioning

confidence: 99%

“…Thus, there is an urgent need to dissect RXRα signaling pathways and to identify and develop new RXRα modulators that have unique properties and improved therapeutic indexes. In this review, we focus on the nongenomic activity of RXRα and highlight recent advances in this field with an emphasis on tRXRα actions [21] and RXRα modulation by targeting alternate binding sites on its surface [56,57] .…”

Section: Introductionmentioning

confidence: 99%

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Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites

Zhang

Chen

et al. 2014

Acta Pharmacol Sin

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Retinoid X receptor-α (RXRα), a unique member of the nuclear receptor superfamily, represents an intriguing and unusual target for pharmacologic interventions and therapeutic applications in cancer, metabolic disorders and neurodegenerative diseases. Despite the fact that the RXR-based drug Targretin (bexarotene) is currently used for treating human cutaneous T-cell lymphoma and the fact that RXRα ligands (rexinoids) show beneficial effects in the treatment of cancer and diseases, the therapeutic potential of RXRα remains unexplored. In addition to its conventional transcription regulation activity in the nucleus, RXRα can act in the cytoplasm to modulate important biological processes, such as mitochondria-dependent apoptosis, inflammation, and phosphatidylinositol 3-kinase (PI3K)/ AKT-mediated cell survival. Recently, new small-molecule-binding sites on the surface of RXRα have been identified, which mediate the regulation of the nongenomic actions of RXRα by a class of small molecules derived from the nonsteroidal anti-inflammatory drug (NSAID) Sulindac. This review discusses the emerging roles of the nongenomic actions of RXRα in the RXRα signaling network, and their possible implications in cancer, metabolic and neurodegenerative disorders, as well as our current understanding of RXRα regulation by targeting alternate binding sites on its surface.

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Section: Novel Surface Binding Sites Of Rxrα As Alternate Sites For Tmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites

Zhang

Chen

et al. 2014

Acta Pharmacol Sin

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“…Recent studies showed that RXRα binding to PML/RARα is absolutely required for the development of acute promeylocytic leukemia (APL) in transgenic mice [53][54][55], demonstrating the oncogenic potential of this protein when it acts inappropriately. Several groups have demonstrated that RXRα is proteolytically cleaved in cancer cells [23,45,51,[56][57][58][59][60], and our illustration that tRXRα could enhance TNFα activation of PI3K/AKT and NF-κB pathways revealed that aberration in RXRα signaling by limited proteolysis plays an active role in cancer development [28,29,[61][62][63][64][65].…”

Section: Rxrα and Cancermentioning

confidence: 56%

“…3), could regulate the biological functions of tRXRα. Compound 23 could inhibit the TNFα-induced interaction between tRXRα and p85α, inhibit AKT activation in vitro and in animals, and induce apoptosis [61]. Compound 23 represents the first example of an RXRα modulator that acts via the co-regulator-binding site rather than the classical LBP.…”

Section: Ligands Targeting the Co-regulator-binding Site Of Trxrαmentioning

confidence: 99%

Targeting truncated RXRα for cancer therapy

Zhang¹,

Zhou²,

Su³

2016

ABBS

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Retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a wellestablished drug target, representing one of the most important targets for pharmacologic interventions and therapeutic applications for cancer. However, how RXRα regulates cancer cell growth and how RXRα modulators suppress tumorigenesis are poorly understood. Altered expression and aberrant function of RXRα are implicated in the development of cancer. Previously, several studies had demonstrated the presence of N-terminally truncated RXRα (tRXRα) proteins resulted from limited proteolysis of RXRα in tumor cells. Recently, we discovered that overexpression of tRXRα can promote tumor growth by interacting with tumor necrosis factor-alpha-induced phosphoinositide 3-kinase and NF-κB signal transduction pathways. We also identified nonsteroidal anti-inflammatory drug Sulindac and analogs as effective inhibitors of tRXRα activities via a unique binding mechanism. This review discusses the emerging roles of tRXRα and modulators in the regulation of cancer cell survival and death as well as inflammation and our recent understanding of tRXRα regulation by targeting the alternate binding sites on its surface.

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“…Among these, the co-regulator-binding site is the most studied. Recently, by employing a docking-based virtual screening approach, Chen et al identified a new RXRα antagonist, named compound 23, which can target the co-regulator-binding site of RXRα [ 77 ]. The compound does not bind to the ligand-binding pocket but to a hydrophobic groove on the surface of RXRα, a region where the binding sites of co-repressor and co-activator overlap [ 77 ].…”

Section: Different Binding Sites Of Rxrα For Drug Targetingmentioning

confidence: 99%

Overview of the structure-based non-genomic effects of the nuclear receptor RXRα

Chen

Zhu

et al. 2018

Cell Mol Biol Lett

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The nuclear receptor RXRα (retinoid X receptor-α) is a transcription factor that regulates the expression of multiple genes. Its non-genomic function is largely related to its structure, polymeric forms and modification. Previous research revealed that some non-genomic activity of RXRα occurs via formation of heterodimers with Nur77. RXRα–Nur77 heterodimers translocate from the nucleus to the mitochondria in response to certain apoptotic stimuli and this activity correlates with cell apoptosis. More recent studies revealed a significant role for truncated RXRα (tRXRα), which interacts with the p85α subunit of the PI3K/AKT signaling pathway, leading to enhanced activation of AKT and promoting cell growth in vitro and in animals. We recently reported on a series of NSAID sulindac analogs that can bind to tRXRα through a unique binding mechanism. We also identified one analog, K-80003, which can inhibit cancer cell growth by inducing tRXRα to form a tetramer, thus disrupting p85α–tRXRα interaction. This review analyzes the non-genomic effects of RXRα in normal and tumor cells, and discusses the functional differences based on RXRα protein structure (structure source: the RCSB Protein Data Bank).Electronic supplementary materialThe online version of this article (10.1186/s11658-018-0103-3) contains supplementary material, which is available to authorized users.

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Identification of a New RXRα Antagonist Targeting the Coregulator-Binding Site

Cited by 30 publications

References 26 publications

Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites

Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites

Targeting truncated RXRα for cancer therapy

Overview of the structure-based non-genomic effects of the nuclear receptor RXRα

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Identification of a New RXRα Antagonist Targeting the Coregulator-Binding Site

Cited by 30 publications

References 26 publications

Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites

Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites

Targeting truncated RXR&alpha; for cancer therapy

Overview of the structure-based non-genomic effects of the nuclear receptor RXRα

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Targeting truncated RXRα for cancer therapy