Department of Pharmacy, Ludwig-Maximilians-Universität (LMU) München, 81377 Munich, Germany.
J Med Chem. 2024 Sep 26;67(18):16598-16611. doi: 10.1021/acs.jmedchem.4c01443. Epub 2024 Sep 5.
The human tailless homologue receptor (TLX) is a ligand-activated transcription factor acting as a 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 their use as a set for target identification and validation studies.
人类无尾同源框受体 (TLX) 是一种配体激活的转录因子，作为神经干细胞内稳态的主调控因子发挥作用。尽管它在神经退行性疾病治疗方面具有广阔的应用前景，但 TLX 配体非常稀缺，这就需要我们去探索 TLX 调节的表型效应和靶标验证。我们系统地研究和优化了通过片段融合获得的 TLX 激动剂支架。结构修饰使我们能够开发出两种具有纳摩尔效力和结合亲和力的 TLX 激动剂。这两种激动剂都表现出良好的化学工具特性，包括高选择性和低毒性。值得注意的是，TLX 激动剂包含不同的支架，显示出很高的化学多样性，可作为一组用于靶标鉴定和验证研究。
