β-连环蛋白信号传导的异常调节与癌症的增殖、侵袭、迁移和转移密切相关，因此，能够抑制该通路的小分子可能具有重要的临床意义。我们的分子模型研究表明，奥美洛昔芬 (ORM)（一种与 β-连环蛋白对接的三苯乙烯分子）及其溴化类似物 (Br-ORM) 能够以相对较少的能量 (-7.6 kcal/mol) 更有效地结合到 β 的活性位点-连环蛋白与亲本 ORM 相比。在此，我们通过 NMR 和 FTIR 报告了 Br-ORM 的合成和表征，以及其在宫颈癌模型中的抗癌活性。 Br-ORM 治疗有效抑制致瘤特征（细胞增殖和集落形成能力等）并诱导细胞凋亡，这一点可通过明显的 PARP 裂解来证明。此外，Br-ORM 处理导致细胞周期停滞在 G1-S 期。机制研究表明，Br-ORM 靶向参与促进上皮间质转化 (EMT) 的关键蛋白，上调 E-钙粘蛋白并抑制 N-钙粘蛋白、波形蛋白、Snail、MMP-2 和 MMP-9 表达即可证明这一点。 Br-ORM 还抑制 β-连环蛋白的表达和核亚细胞定位。因此，与载体对照治疗的小鼠相比，Br-ORM 治疗有效抑制了原位宫颈癌异种移植小鼠模型中的肿瘤生长以及 EMT 相关的变化。总而言之，实验结果表明 Br-ORM 是一种新型、有前途的 β-连环蛋白抑制剂，因此可以作为有效的抗癌小分子用于宫颈癌治疗。© 2023 作者。由美国化学会出版。

Aberrant regulation of β-catenin signaling is strongly linked with cancer proliferation, invasion, migration, and metastasis, thus, small molecules that can inhibit this pathway might have great clinical significance. Our molecular modeling studies suggest that ormeloxifene (ORM), a triphenylethylene molecule that docks with β-catenin, and its brominated analogue (Br-ORM) bind more effectively with relatively less energy (-7.6 kcal/mol) to the active site of β-catenin as compared to parent ORM. Herein, we report the synthesis and characterization of a Br-ORM by NMR and FTIR, as well as its anticancer activity in cervical cancer models. Br-ORM treatment effectively inhibited tumorigenic features (cell proliferation and colony-forming ability, etc.) and induced apoptotic death, as evident by pronounced PARP cleavage. Furthermore, Br-ORM treatment caused cell cycle arrest at the G1-S phase. Mechanistic investigation revealed that Br-ORM targets the key proteins involved in promoting epithelial-mesenchymal transition (EMT), as demonstrated by upregulation of E-cadherin and repression of N-cadherin, Vimentin, Snail, MMP-2, and MMP-9 expression. Br-ORM also represses the expression and nuclear subcellular localization of β-catenin. Consequently, Br-ORM treatment effectively inhibited tumor growth in an orthotopic cervical cancer xenograft mouse model along with EMT associated changes as compared to vehicle control-treated mice. Altogether, experimental findings suggest that Br-ORM is a novel, promising β-catenin inhibitor and therefore can be harnessed as a potent anticancer small molecule for cervical cancer treatment.© 2023 The Authors. Published by American Chemical Society.