March 3, 2026

Systematic Optimization of Fragment TLX Ligands toward Agonism and Inverse Agonism

Puntos clave

TLX ligands were successfully optimized to exhibit both agonism and inverse agonism, enhancing their therapeutic potential.
The structural optimization process revealed potent ligands with effective binding interactions, indicating good ligand efficiency.
A drug fragment screening led to valuable insights on the substructures necessary for modulating TLX activity levels.
These findings highlight the potential for TLX modulation as a strategy for developing neuroprotective therapies.

Resumen

The transcription factor tailless homologue (TLX, NR2E1) maintains persistence of neural stem cells (NSCs) in a proliferating, undifferentiated state, thereby controlling NSC homeostasis and enabling neurogenesis. TLX is responsive to small-molecule ligands, offering potential access to new neuroprotective treatments, but TLX ligands are very rare. Here, we used a drug fragment screening hit as lead to develop TLX modulators and identified substructures tuning activity between agonism and inverse agonism. Structural optimization provided potent TLX activating and inhibiting fragment ligands with validated binding and favorable ligand efficiency for structural extension.

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Cite This Study

Hank et al. (Wed,) studied this question.

synapsesocial.com/papers/69a75cc6c6e9836116a25ef3 https://doi.org/https://doi.org/10.1021/acs.jmedchem.5c02718

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