Discovery of a Novel Small-Molecule Inhibitor that Targets PP2A-{beta}-Catenin Signaling and Restricts Tumor Growth and Metastasis
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); 1791–805. ©2017 AACR.
Source: Molecular Cancer Therapeutics - Category: Cancer & Oncology Authors: Maheshwari, S., Avula, S. R., Singh, A., Singh, L. R., Palnati, G. R., Arya, R. K., Cheruvu, S. H., Shahi, S., Sharma, T., Meena, S., Singh, A. K., Kant, R., Riyazuddin, M., Bora, H. K., Siddiqi, M. I., Gayen, J. R., Sashidhara, K. V., Datta, D. Tags: Small Molecule Therapeutics Source Type: research
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