4.7 Review

Opportunities and challenges in targeting orphan nuclear receptors

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Summary: The three retinoid X receptor subtypes (RXR alpha, RXR beta, RXR gamma) play critical roles in cell proliferation and differentiation, metabolism, and inflammation. Developing subtype-selective ligands for RXRs is challenging due to their wide distribution and adverse effects caused by pan-RXR agonists. By fusing elements of known RXR ligands and making minor structural modifications, we have obtained a new RXR agonist chemotype that has preference for RXR alpha, RXR beta, or RXR gamma. Molecular modeling suggests that different binding conformations and interaction patterns contribute to subtype-selective binding. In a phenotypic adipocyte differentiation experiment, we found that only the RXR alpha selective tool enhanced the adipogenic effects of pioglitazone, indicating the relevance of this subtype in adipogenesis and the suitability of subtype-selective RXR agonist tools for functional cellular studies.

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Oleic acid is an endogenous ligand of TLX/NR2E1 that triggers hippocampal neurogenesis

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Nurr1 Modulation Mediates Neuroprotective Effects of Statins

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Medicinal Chemistry and Chemical Biology of Nurr1 Modulators: An Emerging Strategy in Neurodegeneration

Sabine Willems et al.

Summary: Nuclear receptor related 1 (Nurr1) is a transcription factor with neuroprotective and antineuroinflammatory properties, showing potential as a therapeutic target in neurodegeneration. Recent progress has been made in understanding the structure and mechanisms of Nurr1, and several ligand scaffolds have been discovered.

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Mechanistic Impact of Different Ligand Scaffolds on FXR Modulation Suggests Avenues to Selective Modulators

Jan Heering et al.

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LRH-1 (liver receptor homolog-1) derived affinity peptide ligand to inhibit interactions between beta-catenin and LRH-1 in pancreatic cancer cells: from computational design to experimental validation

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Development and Profiling of Inverse Agonist Tools for the Neuroprotective Transcription Factor Nurr1

Daniel Zaienne et al.

Summary: The study found that indole-based inverse Nurr1 agonists can effectively regulate Nurr1 activity by inhibiting the monomer activity and reducing the receptor's transcriptional activity. These agonists disrupted Nurr1 activity in cell-free experiments and reduced the expression of Nurr1-regulated genes in cells, showing potential to investigate the role of Nurr1 in neuroinflammation, cancer, and beyond.

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The Medicinal Chemistry and Therapeutic Potential of LRH-1 Modulators

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Summary: LRH-1, a ligand-activated transcription factor, is involved in metabolic homeostasis regulation with therapeutic potential in various diseases. However, due to a lack of suitable ligands, the study of pharmacological control over LRH-1 has been insufficiently explored.

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Fragment-like Chloroquinolineamines Activate the Orphan Nuclear Receptor Nurr1 and Elucidate Activation Mechanisms

Sabine Willems et al.

Summary: The study identified fragment-sized Nurr1 agonists that can activate Nurr1 in various cellular environments and enhance gene expression in human astrocytes. These findings provide important insights into Nurr1 regulation.

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Orphan nuclear receptor TLX promotes immunosuppression via its transcriptional activation of PD-L1 in glioma

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Summary: The study identified a positive association between TLX and PD-L1 expression in gliomas, with TLX able to regulate immune suppression through the PD-L1/PD-1 axis. Inhibition of TLX significantly slowed tumor growth, increased cytotoxic lymphocyte infiltration, and decreased PD-L1 positive cells, suggesting potential therapeutic implications for targeting TLX in glioma immune therapy.

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Summary: TLX, an orphan member of the nuclear receptor superfamily, plays a crucial role in regulating the proliferation of neural stem cells and retinal progenitor cells. Dysregulation of TLX expression has been associated with various pathological conditions, including abnormal brain development, psychiatric disorders, retinopathies, metabolic disease, and malignant neoplasms. Despite the lack of an identified endogenous ligand, TLX has been suggested as a potential therapeutic target in different diseases, particularly cancer.

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The Transcriptional Repressor Orphan Nuclear Receptor TLX Is Responsive to Xanthines

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Summary: TLX, an orphan member of the nuclear receptor superfamily, is primarily known for its repressive nature in regulating the proliferation of neural stem cells and retinal progenitor cells. Dysregulation and abnormal expression of TLX have been linked to various pathological conditions, including abnormal brain development, psychiatric disorders, retinopathies, metabolic disease, and malignant neoplasm. Despite the lack of an identified endogenous ligand, potential synthetic and natural TLX ligands have been suggested, making this receptor a potential therapeutic target, particularly in cancer research.

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International Union of Pharmacology.: LXIV.: Estrogen receptors

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