ArticleJournal of medicinal chemistry2026
Systematic Optimization of Fragment TLX Ligands toward Agonism and Inverse Agonism.
Article in Journal of medicinal chemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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7 authors.
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Abstract
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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