ArticlePloS one2014
The human orphan nuclear receptor tailless (TLX, NR2E1) is druggable.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
25 citing papers in PubMed, 53 citations in OpenAlex.
- An Activator of Tailless' Repressor Function Stimulates Anti-Neurodegenerative Gene Expression.Journal of medicinal chemistry · 2026Article
- Systematic Optimization of Fragment TLX Ligands toward Agonism and Inverse Agonism.Journal of medicinal chemistry · 2026Article
- Structural Elucidation and Covalent Modulation of the Autorepressed Orphan Nuclear Receptor NR2F6.ACS chemical biology · 2025Article
- Comparative Evaluation and Profiling of Chemical Tools for the Nuclear Hormone Receptor Family 2.ACS pharmacology & translational science · 2025Article
- Nuclear receptor TLX functions to promote cancer stemness and EMT in prostate cancer via its direct transactivation of CD44 and stem cell-regulatory transcription factors.British journal of cancer · 2024Article
- Oleic acid is an endogenous ligand of TLX/NR2E1 that triggers hippocampal neurogenesis.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- The Ets protein Pointed P1 represses Asense expression in type II neuroblasts by activating Tailless.PLoS genetics · 2022Article
- The Transcriptional Repressor Orphan Nuclear Receptor TLX Is Responsive to Xanthines.ACS pharmacology & translational science · 2021Article
- TLX, an Orphan Nuclear Receptor With Emerging Roles in Physiology and Disease.Endocrinology · 2021Review
- Glial PAMPering and DAMPening of Adult Hippocampal Neurogenesis.Brain sciences · 2021Review
- The orphan nuclear receptor TLX: an emerging master regulator of cross-talk between microglia and neural precursor cells.Neuronal signaling · 2019Article
- Aberrant transcriptomes and DNA methylomes define pathways that drive pathogenesis and loss of brain laterality/asymmetry in schizophrenia and bipolar disorder.American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics · 2019Article
- Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor.Molecules (Basel, Switzerland) · 2018Article
- Developmental pathway genes and neural plasticity underlying emotional learning and stress-related disorders.Learning & memory (Cold Spring Harbor, N.Y.) · 2017Review
- TLX-Its Emerging Role for Neurogenesis in Health and Disease.Molecular neurobiology · 2017Review
- Article
- Co-activator candidate interactions for orphan nuclear receptor NR2E1.BMC genomics · 2016Article
- Antimitotic activity of DY131 and the estrogen-related receptor beta 2 (ERRβ2) splice variant in breast cancer.Oncotarget · 2016Article
- The Orphan Nuclear Receptor TLX/NR2E1 in Neural Stem Cells and Diseases.Neuroscience bulletin · 2016Review
- The Orphan Nuclear Receptor TLX Is an Enhancer of STAT1-Mediated Transcription and Immunity to Toxoplasma gondii.PLoS biology · 2015Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 4 institutions in 1 country.
Funding
Abstract
Nuclear receptors (NRs) are an important group of ligand-dependent transcriptional factors. Presently, no natural or synthetic ligand has been identified for a large group of orphan NRs. Small molecules to target these orphan NRs will provide unique resources for uncovering regulatory systems that impact human health and to modulate these pathways with drugs. The orphan NR tailless (TLX, NR2E1), a transcriptional repressor, is a major player in neurogenesis and Neural Stem Cell (NSC) derived brain tumors. No chemical probes that modulate TLX activity are available, and it is not clear whether TLX is druggable. To assess TLX ligand binding capacity, we created homology models of the TLX ligand binding domain (LBD). Results suggest that TLX belongs to an emerging class of NRs that lack LBD helices α1 and α2 and that it has potential to form a large open ligand binding pocket (LBP). Using a medium throughput screening strategy, we investigated direct binding of 20,000 compounds to purified human TLX protein and verified interactions with a secondary (orthogonal) assay. We then assessed effects of verified binders on TLX activity using luciferase assays. As a result, we report identification of three compounds (ccrp1, ccrp2 and ccrp3) that bind to recombinant TLX protein with affinities in the high nanomolar to low micromolar range and enhance TLX transcriptional repressive activity. We conclude that TLX is druggable and propose that our lead compounds could serve as scaffolds to derive more potent ligands. While our ligands potentiate TLX repressive activity, the question of whether it is possible to develop ligands to de-repress TLX activity remains open.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.