| Autor: |
Rivas DR; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA., Dela Cerna MVC; Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, 40202, USA., Smith CN; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA., Sampathi S; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA., Patty BG; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA., Lee D; Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, 40202, USA. donghan.lee@louisville.edu.; Department of Medicine, James Graham Brown Cancer Center, Louisville, KY, 40202, USA. donghan.lee@louisville.edu., Blackburn JS; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA. jsblackburn@uky.edu.; Markey Cancer Center, Lexington, KY, 40536, USA. jsblackburn@uky.edu. |
| Abstrakt: |
Protein tyrosine phosphatase 4A3 (PTP4A3 or PRL-3) is highly expressed in a variety of cancers, where it promotes tumor cell migration and metastasis leading to poor prognosis. Despite its clinical significance, small molecule inhibitors of PRL-3 are lacking. Here, we screened 1443 FDA-approved drugs for their ability to inhibit the activity of the PRL phosphatase family. We identified five specific inhibitors for PRL-3 as well as one selective inhibitor of PRL-2. Additionally, we found nine drugs that broadly and significantly suppressed PRL activity. Two of these broad-spectrum PRL inhibitors, Salirasib and Candesartan, blocked PRL-3-induced migration in human embryonic kidney cells with no impact on cell viability. Both drugs prevented migration of human colorectal cancer cells in a PRL-3 dependent manner and were selective towards PRLs over other phosphatases. In silico modeling revealed that Salirasib binds a putative allosteric site near the WPD loop of PRL-3, while Candesartan binds a potentially novel targetable site adjacent to the CX 5 R motif. Inhibitor binding at either of these sites is predicted to trap PRL-3 in a closed conformation, preventing substrate binding and inhibiting function. |
