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

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.