Development of Tailless Homologue Receptor (TLX) Agonist Chemical Tools

The human tailless
homologue receptor (TLX) is a ligand-activated
transcription factor acting as a master regulator of neural stem cell
homeostasis. Despite its promising potential in neurodegenerative
disease treatment, TLX ligands are rare but required to explore phenotypic
effects of TLX modulation and for target validation. We have systematically
studied and optimized a TLX agonist scaffold obtained by fragment
fusion. Structural modification enabled the development of two TLX
agonists endowed with nanomolar potency and binding affinity. Both
exhibited favorable chemical tool characteristics including high selectivity
and low toxicity. Most notably, the TLX agonists comprise different
scaffolds and display high chemical diversity, enabling their use
as a set for target identification and validation studies.