Development of\nTailless Homologue Receptor (TLX) Agonist\nChemical Tools

The human tailless\nhomologue receptor (TLX) is a ligand-activated\ntranscription factor acting as a master regulator of neural stem cell\nhomeostasis. Despite its promising potential in neurodegenerative\ndisease treatment, TLX ligands are rare but required to explore phenotypic\neffects of TLX modulation and for target validation. We have systematically\nstudied and optimized a TLX agonist scaffold obtained by fragment\nfusion. Structural modification enabled the development of two TLX\nagonists endowed with nanomolar potency and binding affinity. Both\nexhibited favorable chemical tool characteristics including high selectivity\nand low toxicity. Most notably, the TLX agonists comprise different\nscaffolds and display high chemical diversity, enabling their use\nas a set for target identification and validation studies.