Discovery of a Novel Small-Molecule Inhibitor that Targets PP2A-β-Catenin Signaling and Restricts Tumor Growth and Metastasis

Molecular Cancer Therapeutics
Shrankhla MaheshwariDipak Datta

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.

References

Sep 4, 1998·Science·T C HeK W Kinzler
Aug 10, 2000·The British Journal of Surgery·B P WijnhovenM Pignatelli
Dec 26, 2001·Proceedings of the National Academy of Sciences of the United States of America·D YanL T Williams
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Jul 19, 2005·Nature Reviews. Molecular Cell Biology·Barry M Gumbiner
Aug 19, 2005·Current Opinion in Cell Biology·Pamela CowinSarah J Hatsell
Jun 8, 2006·Neoplasia : an International Journal for Oncology Research·Gang ZengSatdarshan P S Monga
Apr 5, 2007·Nature Protocols·Vanicha Vichai, Kanyawim Kirtikara
Jul 14, 2007·Current Medicinal Chemistry·Cláudio Viegas-JuniorCarlos Alberto Manssour Fraga
Jul 1, 2008·Biochimica Et Biophysica Acta·Pieter J A EichhornRené Bernards
Aug 30, 2008·Gastroenterology·Patrick W HeiserMatthias Hebrok
Apr 29, 2009·Journal of Computational Chemistry·Garrett M MorrisArthur J Olson
Feb 26, 2010·Cold Spring Harbor Perspectives in Biology·Julian Heuberger, Walter Birchmeier
Nov 13, 2010·Bioorganic & Medicinal Chemistry Letters·Koneni V SashidharaSudhir Sinha
Apr 15, 2011·The Journal of Clinical Investigation·Eugenia C Pacheco-PinedoEdward E Morrisey
May 5, 2011·Journal of Computational Chemistry·Vincent ZoeteOlivier Michielin
Oct 11, 2012·North American Journal of Medical Sciences·Tahrin Mahmood, Ping-Chang Yang
Nov 22, 2012·Cold Spring Harbor Perspectives in Biology·Jennifer L Stamos, William I Weis
Jan 5, 2013·European Journal of Medicinal Chemistry·Koneni V SashidharaSurendar Reddy Bathula
May 23, 2014·Bioorganic & Medicinal Chemistry Letters·Shikha S ChauhanPrem M S Chauhan
Feb 6, 2015·CA: a Cancer Journal for Clinicians·Lindsey A TorreAhmedin Jemal

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cadherins and Catenins

Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule (CAM) that is important in the formation of adherens junctions to bind cells with each other. Catenins are a family of proteins found in complexes with cadherin cell adhesion molecules of animal cells: alpha-catenin can bind to β-catenin and can also bind actin. β-catenin binds the cytoplasmic domain of some cadherins. Discover the latest research on cadherins and catenins here.

Adherens Junctions

An adherens junction is defined as a cell junction whose cytoplasmic face is linked to the actin cytoskeleton. They can appear as bands encircling the cell (zonula adherens) or as spots of attachment to the extracellular matrix (adhesion plaques). Adherens junctions uniquely disassemble in uterine epithelial cells to allow the blastocyst to penetrate between epithelial cells. Discover the latest research on adherens junctions here.