Propranolol Activates the Orphan Nuclear Receptor TLX to Counteract Proliferation and Migration of Glioblastoma Cells

J Med Chem. 2021 Jun 24;64(12):8727-8738. doi: 10.1021/acs.jmedchem.1c00733. Epub 2021 Jun 11.


The ligand-sensing transcription factor tailless homologue (TLX, NR2E1) is an essential regulator of neuronal stem cell homeostasis with appealing therapeutic potential in neurodegenerative diseases and central nervous system tumors. However, knowledge on TLX ligands is scarce, providing an obstacle to target validation and medicinal chemistry. To discover TLX ligands, we have profiled a drug fragment collection for TLX modulation and identified several structurally diverse agonists and inverse agonists of the nuclear receptor. Propranolol evolved as the strongest TLX agonist and promoted TLX-regulated gene expression in human glioblastoma cells. Structure-activity relationship elucidation of propranolol as a TLX ligand yielded a structurally related negative control compound. In functional cellular experiments, we observed an ability of propranolol to counteract glioblastoma cell proliferation and migration, while the negative control had no effect. Our results provide a collection of TLX modulators as initial chemical tools and set of lead compounds and support therapeutic potential of TLX modulation in glioblastoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Cell Proliferation / drug effects*
  • Glioblastoma / drug therapy*
  • HEK293 Cells
  • Humans
  • Molecular Structure
  • Orphan Nuclear Receptors
  • Propranolol / pharmacology*
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Structure-Activity Relationship


  • NR2E1 protein, human
  • Orphan Nuclear Receptors
  • Receptors, Cytoplasmic and Nuclear
  • Propranolol