ArticleJournal of medicinal chemistry2026
An Activator of Tailless' Repressor Function Stimulates Anti-Neurodegenerative Gene Expression.
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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9 authors.
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Abstract
The transcription factor tailless (TLX, NR2E1) is expressed in neuronal stem cells and retinal progenitor cells and is thought to maintain their self-renewal by balancing proliferation and differentiation. It is considered as a master regulator of neurogenesis and a promising target in neurodegeneration. Here, we developed highly potent and selective activators of TLX' transcriptional repressor activity by systematic extension of previously optimized fragment TLX ligands and tuning of the substitution pattern. An optimized TLX activator with nanomolar potency and pronounced selectivity was studied for its transcriptomic effects by RNAseq, which demonstrated upregulation of genes associated with ATP production, lysosomal function, and vesicular transport. Moreover, the mitochondrial quality control-associated PTEN-induced kinase 1 (PINK1) was induced, and the amyloidogenic β-secretase (BACE) was downregulated, supporting anti-neurodegenerative effects of TLX modulation on the transcriptional level.
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