Dysregulation of the Wnt signaling pathway is an underlying mechanism in multiple diseases, particularly in cancer. Until recently, identifying agents that target this pathway has been difficult and as a result, no approved drugs exist that specifically target this pathway. We reported previously that the anthelmintic drug Niclosamide inhibits the Wnt/β-catenin signaling pathway and suppresses colorectal cancer cell growth in vitro and in vivo. In an effort to build on this finding, we sought to discover new Wnt/β-catenin inhibitors that expanded the chemotype structural diversity. Here, we asked a specific SAR question unresolved in previous SAR studies of Niclosamide's inhibition of Wnt/β-catenin signaling to identify a new structural class of Wnt/β-catenin signaling inhibitors based on a triazole motif. Similar to Niclosamide, we found that the new triazole derivatives internalized Frizzled-1 GFP receptors, inhibited Wnt/β-catenin signaling in the TOPflash assay and reduced Wnt/β-catenin target gene levels in CRC cells harboring mutations in the Wnt pathway. Moreover, in pilot SAR studies, we found the Wnt/β-catenin SAR trends in the anilide region were generally similar between the two chemical classes of inhibitors. Overall, these studies demonstrate the ability to use the SAR of the Niclosamide salicylanilide chemical class to expand the structural diversity of Wnt/β-catenin inhibitors.

中文翻译：

---

基于Niclosamide化学型鉴定Wnt /β-catenin信号的新型三唑抑制剂。

Wnt信号通路的失调是多种疾病（尤其是癌症）的潜在机制。直到最近，鉴定靶向该途径的药物一直很困难，结果，尚不存在专门针对该途径的已批准药物。我们以前曾报道过，驱虫药Niclosamide抑制Wnt /β-catenin信号通路并在体外和体内抑制结直肠癌细胞的生长。在此基础上，我们努力寻找新的Wnt /β-catenin抑制剂，以扩大化学型的结构多样性。在这里，我们问了一个具体的SAR问题，在以前的SAR研究中，氯硝酰胺对Wnt /β-catenin信号传导的抑制作用尚未得到解决，以基于三唑基序识别Wnt /β-catenin信号传导抑制剂的新结构类型。与尼氯胺类似，我们发现，新的三唑衍生物内化了Frizzled-1 GFP受体，在TOPflash分析中抑制了Wnt /β-catenin信号传导，并降低了Wnt途径中突变的CRC细胞的Wnt /β-catenin靶基因水平。此外，在先导性SAR研究中，我们发现两种化学类型的抑制剂在苯胺化物区域的Wnt /β-cateninSAR趋势大致相似。总体而言，这些研究证明了使用尼氯酰胺水杨酰苯胺化学类别的SAR来扩大Wnt /β-catenin抑制剂的结构多样性的能力。我们发现在两种化学类别的抑制剂之间，苯胺化物区域的Wnt /β-cateninSAR趋势大致相似。总体而言，这些研究证明了使用尼氯酰胺水杨酰苯胺化学类别的SAR来扩大Wnt /β-catenin抑制剂的结构多样性的能力。我们发现在两种化学类别的抑制剂之间，苯胺化物区域的Wnt /β-cateninSAR趋势大致相似。总体而言，这些研究证明了使用尼氯酰胺水杨酰苯胺化学类别的SAR来扩大Wnt /β-catenin抑制剂的结构多样性的能力。