The gain of cell motility is an essential prerequisite for cancer metastasis. The ubiquitin ligase subunit WD repeat and SOCS box-containing 1 (WSB1) has been demonstrated to regulate hypoxia-driven tumor cell migration. However, there is still a lack of methods for discovering inhibitors targeting the WSB1 axis. Here, we employed phenotypic screening models and identified compound 4 that displayed migration inhibitory activity against WSB1-overexpressing cells. Further studies indicated that it may function as a WSB1 degrader, thus leading to the accumulation of the Rho guanosine diphosphate dissociation inhibitor 2 (RhoGDI2) protein, reversing the expression of downstream F-actin and formation of membrane ruffles, and disturbing the migration capacity of cancer cells. Moreover, compound 4 exhibited a promising in vivo anticancer metastatic effects. Our findings show the discovery of a new WSB1 degrader, providing a unique solution for the treatment of cancer metastasis.

中文翻译：

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发现 5,6-双（4-甲氧基-3-甲基苯基）吡啶-2-胺作为 WSB1 降解剂抑制癌细胞转移

细胞运动的获得是癌症转移的必要先决条件。泛素连接酶亚基 WD 重复和含有 SOCS 盒的 1 (WSB1) 已被证明可以调节缺氧驱动的肿瘤细胞迁移。然而，仍然缺乏发现针对 WSB1 轴的抑制剂的方法。在这里，我们采用了表型筛选模型并确定了对 WSB1 过表达细胞显示迁移抑制活性的化合物4。进一步的研究表明，它可能作为 WSB1 降解剂，从而导致 Rho 鸟苷二磷酸解离抑制剂 2 (RhoGDI2) 蛋白的积累，逆转下游 F-肌动蛋白的表达和膜褶皱的形成，并干扰了癌细胞。此外，化合物4表现出有希望的体内抗癌转移作用。我们的研究结果表明发现了一种新的 WSB1 降解剂，为治疗癌症转移提供了独特的解决方案。