Carboxylesterase Notum is a negative regulator of the Wnt signaling pathway. There is an emerging understanding of the role Notum plays in disease, supporting the need to discover new small-molecule inhibitors. A crystallographic X-ray fragment screen was performed, which identified fragment hit 1,2,3-triazole 7 as an attractive starting point for a structure-based drug design hit-to-lead program. Optimization of 7 identified oxadiazol-2-one 23dd as a preferred example with properties consistent with drug-like chemical space. Screening 23dd in a cell-based TCF/LEF reporter gene assay restored the activation of Wnt signaling in the presence of Notum. Mouse pharmacokinetic studies with oral administration of 23dd demonstrated good plasma exposure and partial blood–brain barrier penetration. Significant progress was made in developing fragment hit 7 into lead 23dd (>600-fold increase in activity), making it suitable as a new chemical tool for exploring the role of Notum-mediated regulation of Wnt signaling.

中文翻译：

---

5-Phenyl-1,3,4-oxadiazol-2(3H)-ones 是通过优化结晶片段筛选命中确定的 Notum 羧酸酯酶活性的有效抑制剂

Carboxylesterase Notum 是 Wnt 信号通路的负调节剂。人们对 Notum 在疾病中的作用有了新的认识，支持发现新的小分子抑制剂的必要性。进行了晶体学 X 射线碎片筛选，确定碎片命中 1,2,3-三唑7作为基于结构的药物设计命中先导计划的一个有吸引力的起点。7的优化确定 oxadiazol-2-one 23dd是一个优选的例子，其特性与类药物化学空间一致。在基于细胞的 TCF/LEF 报告基因测定中筛选23dd恢复了在 Notum 存在下 Wnt 信号传导的激活。口服23dd的小鼠药代动力学研究表现出良好的血浆暴露和部分血脑屏障穿透。在将片段 hit 7发展为前导23dd （活性增加 > 600 倍）方面取得了重大进展，使其适合作为探索 Notum 介导的 Wnt 信号调节作用的新化学工具。