Abstract
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.
Highlights
Cancer is the second major killer of human population as per WHO estimates for 2012, and by 2030, the global cancer burden is expected to rise to 21.7 million new cancer cases and 13 million cancer-related deaths [1]
Utilizing our molecular hybridization approach, we have synthesized a series of chalcone–semicarbazone hybrids containing 17 compounds, and details of their synthesis and different qualitative and quantitative analyses are provided in Supplementary Figs
Molecular hybridization of different pharmacophores offers the possibility of engagement of different target proteins together to control both tumor growth and metastasis
Summary
Cancer is the second major killer of human population as per WHO estimates for 2012, and by 2030, the global cancer burden is expected to rise to 21.7 million new cancer cases and 13 million cancer-related deaths [1]. Cancer metastasis is the major reason of cancer-related morbidity and mortality. Loss of epithelial properties as well as acquisition of mesenchymal characteristics is one of the key features of early metastatic process [2]. E-Cadherin and b-catenin together play a crucial role in initial dissemination of metastatic cells. Nuclear displacement of active b-catenin and its recruitment to the cell surface along with Ecadherin firms cell-to-cell adhesion and prevents an early release of prometastatic cells [3, 4]. In the absence of E-cadherin, b-catenin is phosphorylated in the cytoplasm in a multiprotein destruc-
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
