The potential as a cancer therapeutic target of the recently reported hotspot binding region close to Lys508 of the β-catenin armadillo repeat domain was not exhaustively explored. In order to get more insight, we synthesized novel N-(heterocyclylphenyl)benzenesulfonamides 6–28. The new compounds significantly inhibited Wnt-dependent transcription as well as SW480 and HCT116 cancer cell proliferation. Compound 25 showed binding mode consistent with this hotspot binding region. Compound 25 inhibited the growth of SW480 and HCT116 cancer cells with IC₅₀’s of 2 and 0.12 μM, respectively, and was superior to the reference compounds 5 and 5-FU. 25 inhibited the growth of HCT-116 xenografted in BALB/C^nu/nu mice, reduced the expression of the proliferation marker Ki67, and significantly affected the expression of cancer-related genes. After incubation with human and mouse liver microsomes, 25 showed a higher metabolic stability than 5. Compound 25 aims to be a promising lead for the development of colorectal cancer anticancer therapies.

中文翻译：

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N-（4-（1H-咪唑-1-基）苯基）-4-氯苯磺酰胺的开发，一种新型强效β-连环蛋白抑制剂，具有增强的抗肿瘤活性和代谢稳定性


最近报道的靠近 β-catenin 犰狳重复结构域 Lys508 的热点结合区作为癌症治疗靶点的潜力并未得到详尽探索。为了获得更多见解，我们合成了新型 N-（杂环基苯基）苯磺酰胺 6-28。新化合物显著抑制 Wnt 依赖性转录以及 SW480 和 HCT116 癌细胞增殖。化合物 25 显示出与该热点结合区域一致的结合模式。化合物 25 抑制 SW480 和 HCT116 癌细胞的生长，IC₅₀ 分别为 2 和 0.12 μM，优于参考化合物 5 和 5-FU。25 抑制 BALB/C^nu/nu 小鼠异种移植 HCT-116 的生长，降低增殖标志物 Ki67 的表达，并显着影响癌症相关基因的表达。与人和小鼠肝脏微粒体孵育后，25 表现出比 5 更高的代谢稳定性。Compound 25 旨在成为结直肠癌抗癌疗法开发的有前途的先导药物。