Molecular hybridization of different pharmacophores to tackle both tumor growth and metastasis by a single molecular entity can be very effective and unique if the hybrid product shows drug-like properties. Here, we report synthesis and discovery of a novel small-molecule inhibitor of PP2A–β-catenin signaling that limits both in vivo tumor growth and metastasis. Our molecular hybridization approach resulted in cancer cell selectivity and improved drug-like properties of the molecule. Inhibiting PP2A and β-catenin interaction by selectively engaging PR55α-binding site, our most potent small-molecule inhibitor diminished the expression of active β-catenin and its target proteins c-Myc and Cyclin D1. Furthermore, it promotes robust E-cadherin upregulation on the cell surface and increases β-catenin–E-Cadherin association, which may prevent dissemination of metastatic cells. Altogether, we report synthesis and mechanistic insight of a novel drug-like molecule to differentially target β-catenin functionality via interacting with a particular subunit of PP2A. Mol Cancer Ther; 16(9); 1–15. ©2017 AACR.

中文翻译：

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靶向PP2A-β-Catenin信号传导并限制肿瘤生长和转移的新型小分子抑制剂的发现。

如果杂种产物显示出类似药物的性质，则通过单个分子实体来解决肿瘤生长和转移的不同药效团的分子杂交将是非常有效且独特的。在这里，我们报道了一种新型的小分子PP2A–β-catenin信号抑制剂的合成和发现，该抑制剂既限制了体内肿瘤的生长，也限制了其转移。我们的分子杂交方法导致癌细胞具有选择性并改善了该分子的类药物特性。通过选择性地参与PR55α结合位点来抑制PP2A和β-catenin的相互作用，我们最有效的小分子抑制剂降低了活性β-catenin及其靶蛋白c-Myc和Cyclin D1的表达。此外，它还能促进细胞表面E-cadherin的上调，并增强β-catenin-E-Cadherin的结合，这可能会阻止转移性细胞的扩散。总而言之，我们报告了通过与PP2A的特定亚基相互作用，以差异方式靶向β-catenin功能的新型药物样分子的合成和机理见解。分子癌疗法；16（9）; 1-15。©2017 AACR。