Development of tailless homologue receptor (TLX) agonist chemical tools

07 August 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

The tailless homologue receptor (TLX) is a ligand-activated transcription factor acting as 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 a use as set for target identification and validation studies.

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