Structures and regulation of non-X orphan nuclear receptors: A retinoid hypothesis

Zhi, Xiaoyong; Zhou, Xuemei; Melcher, Karsten; Xu, H. Eric

doi:10.1016/j.jsbmb.2015.06.012

Cited by 10 publications

(3 citation statements)

References 212 publications

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“…Accordingly, it is also difficult to find inhibitors for orphan nuclear receptors. However, the x-ray structure of LBD in multiple orphan members, including COUP-TFII, Nurr1, PNR, TR4, and REV-ERB, reveals that they all have a putative hydrophobic ligand-binding pocket with different sizes (16,27,28). Recent evidence also shows that small-molecule compounds, which bind to classical binding pockets, surface cavities, and cryptic sites or induce protein conformation changes, may regulate the activity of orphan nuclear receptors, suggesting that the orphan nuclear receptor might be targetable or druggable.…”

Section: Discussionmentioning

confidence: 99%

Small-molecule inhibitor targeting orphan nuclear receptor COUP-TFII for prostate cancer treatment

et al. 2020

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The orphan nuclear receptor COUP-TFII is expressed at a low level in adult tissues, but its expression is increased and shown to promote progression of multiple diseases, including prostate cancer, heart failure, and muscular dystrophy. Suppression of COUP-TFII slows disease progression, making it an intriguing therapeutic target. Here, we identified a potent and specific COUP-TFII inhibitor through high-throughput screening. The inhibitor specifically suppressed COUP-TFII activity to regulate its target genes. Mechanistically, the inhibitor directly bound to the COUP-TFII ligand-binding domain and disrupted COUP-TFII interaction with transcription regulators, including FOXA1, thus repressing COUP-TFII activity on target gene regulation. Through blocking COUP-TFII’s oncogenic activity in prostate cancer, the inhibitor efficiently exerted a potent antitumor effect in xenograft mouse models and patient-derived xenograft models. Our study identified a potent and specific COUP-TFII inhibitor that may be useful for the treatment of prostate cancer and possibly other diseases.

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Section: Discussionmentioning

confidence: 99%

Small-molecule inhibitor targeting orphan nuclear receptor COUP-TFII for prostate cancer treatment

et al. 2020

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“… 7 NRs are ligand-inducible transcription factors that alter transcription rates, as well as the subsequent expression levels of their target genes by contacting their promoter or enhancer sequences at specific recognition sites. 8 , 9 , 10 P parα is activated by PPs, and in response to PPs activation, P parα heterodimerizes with retinoid X receptor α (R xrα ). 11 , 12 Additionally, after the recruitment of co-activators, P parα binds to the peroxisome proliferator response element (PPRE) in the promoter or enhancer region of those downstream target genes.…”

Section: Introductionmentioning

confidence: 99%

Alleviation of Toxicity Caused by Overactivation of Pparα through Pparα-Inducible miR-181a2

Cheng

Wei

Xie

et al. 2017

Molecular Therapy - Nucleic Acids

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Widely varied compounds, including certain plasticizers, hypolipidemic drugs (e.g., ciprofibrate, fenofibrate, WY-14643, and clofibrate), agrochemicals, and environmental pollutants, are peroxisome proliferators (PPs). Appropriate dose of PPs causes a moderate increase in the number and size of peroxisomes and the expression of genes encoding peroxisomal lipid-metabolizing enzymes. However, high-dose PPs cause varied harmful effects. Chronic administration of PPs to mice and rats results in hepatomegaly and ultimately carcinogenesis. Nuclear receptor protein peroxisome proliferator-activated receptor-α (Pparα) was shown to be required for this process. However, biological adaptations to minimize this risk are poorly understood. In this study, we found that miR-181a2 expression was induced by the Pparα agonist WY-14643. Moreover, exogenous expression of miR-181a-5p dramatically alleviated the cell toxicity caused by overactivation of Pparα. Further studies showed that miR-181a-5p directly targeted the Pparα 3′ untranslated region and depressed the Pparα protein level. This study identified a feedback loop between miR-181a-5p and Pparα, which allows biological systems to approach a balance when Pparα is overactivated.

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“…However, only 17 NRs have been successfully targeted in the clinic . Of the remaining NRs, many respond to abundant lipids and lipid metabolites, and elucidating native ligands and synthetic modulators has been challenging. , …”

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confidence: 99%

Development of a Versatile and Sensitive Direct Ligand Binding Assay for Human NR5A Nuclear Receptors

D’Agostino

Flynn

Cornelison

et al. 2019

ACS Med. Chem. Lett.

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The human NR5A nuclear receptors, steroidogenic factor‐1 (SF‐1, NR5A1) and liver receptor homolog‐1 (LRH‐1, NR5A2), are phospholipid‐sensing regulators of steroidogenesis, development, and metabolism. Their control of such diverse biological processes renders them attractive pharmacological targets for the treatment of several cancers and metabolic diseases such as obesity, type II diabetes, and non‐alcoholic fatty liver disease. However, the evaluation of candidate endogenous ligands and the development of small molecule modulators have been hindered by the lack of a robust direct binding assay. Using a structure‐guided approach, we recently developed a potent NR5A agonist (EC50 of 15 nM) targeting the ligand‐binding pocket. We have leveraged this molecule to create a high‐affinity fluorescent probe that binds SF‐1 and LRH‐1 with affinites of 12 nM and 1 nM, respectively. This probe has enabled the creation of a fluorescence polarization (FP)‐based competition assay suitable for both synthetic small molecules and mammalian phospholipids. FP is solution‐based, allowing proteins to retain their native conformation, and the competition format of the assay ensures that binding will only be detected in the ligand‐binding pocket. We have found that for a set of 25 LRH‐1 agonists derived from the previously‐reported RJW100 scaffold, affinities determined by FP correlate with potencies in a luciferase reporter assay, suggesting that in vitro binding affinity may be predictive of in‐cell activity for this class of molecule. Moreover, binding affinities reported for other NR5A agonists harboring different chemical scaffolds agree with our FP‐based measurements. Finally, we show that the previously‐reported dilauroylphosphatidylcholine agonist binds LRH‐1 with a Ki of 80 nM, suggesting that this assay may be used to evaluate candidate endogenous ligands for these receptors. Support or Funding Information R01 DK115213 02EHD has additional support from the National Science Foundation Graduate Research Fellowship and the Emory University NIH‐5T32GM008367‐27. SGM has additional support from F31 DK111171 03. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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Structures and regulation of non-X orphan nuclear receptors: A retinoid hypothesis

Cited by 10 publications

References 212 publications

Small-molecule inhibitor targeting orphan nuclear receptor COUP-TFII for prostate cancer treatment

Small-molecule inhibitor targeting orphan nuclear receptor COUP-TFII for prostate cancer treatment

Alleviation of Toxicity Caused by Overactivation of Pparα through Pparα-Inducible miR-181a2

Development of a Versatile and Sensitive Direct Ligand Binding Assay for Human NR5A Nuclear Receptors

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