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. Further, 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.
- Received September 1, 2016.
- Revision received March 8, 2017.
- Accepted May 4, 2017.
- Copyright ©2017, American Association for Cancer Research.