Aberrant activation of the WNT/β-catenin signaling pathway is implicated in various types of cancers. Inhibitors targeting the Wnt signaling pathway are intensively studied in the current cancer research field, the outcomes of which remain to be determined. In this study, we have attempted to discover novel potent WNT/β-catenin pathway inhibitors through tankyrase 1/2 structure-based virtual screening. After screening more than 13.4 million compounds through molecular docking, we experimentally verified one compound, LZZ-02, as the most potent inhibitor out of 11 structurally representative top hits. LiCl-induced HEK293 cells containing TOPFlash reporter showed that LZZ-02 inhibited the transcriptional activity of β-catenin with an IC50 of 10 ± 1.2 μM. Mechanistically, LZZ-02 degrades the expression of β-catenin by stabilizing axin 2, thereby diminishing downstream proteins levels, including c-Myc and cyclin D1. LZZ-02 also inhibits the growth of colonic carcinoma cell harboring constitutively active β-catenin. More importantly, LZZ-02 effectively shrinks tumor xenograft derived from colonic cell lines. Our study successfully identified a novel tankyrase 1/2 inhibitor and shed light on a novel strategy for developing inhibitors targeting the WNT/β-catenin signaling axis.

中文翻译：

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通过基于端锚聚合酶 1/2 结构的虚拟筛选发现 WNT/β-连环蛋白通路的新型抑制剂

WNT/β-catenin 信号通路的异常激活与多种癌症有关。目前癌症研究领域正在深入研究靶向 Wnt 信号通路的抑制剂，其结果仍有待确定。在这项研究中，我们试图通过基于端锚聚合酶 1/2 结构的虚拟筛选来发现新型有效的 WNT/β-连环蛋白通路抑制剂。在通过分子对接筛选了超过 1340 万种化合物后，我们通过实验验证了一种化合物 LZZ-02，它是 11 种具有结构代表性的热门化合物中最有效的抑制剂。LiCl 诱导的含有 TOPFlash 报告基因的 HEK293 细胞显示 LZZ-02 抑制 β-连环蛋白的转录活性，IC50 为 10 ± 1.2 μM。从机制上讲，LZZ-02 通过稳定 axin 2 来降低 β-catenin 的表达，从而降低下游蛋白质水平，包括 c-Myc 和细胞周期蛋白 D1。LZZ-02 还抑制含有组成型活性 β-连环蛋白的结肠癌细胞的生长。更重要的是，LZZ-02 有效地缩小了源自结肠细胞系的肿瘤异种移植物。我们的研究成功鉴定了一种新型端锚聚合酶 1/2 抑制剂，并阐明了开发靶向 WNT/β-catenin 信号轴的抑制剂的新策略。