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 CX5R motif. Inhibitor binding at either of these sites is predicted to trap PRL-3 in a closed conformation, preventing substrate binding and inhibiting function.
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This research was supported by a St. Baldrick’s Foundation Research Grant, and NIH grants DP2CA228043 and R37CA227656 (to J.S. Blackburn). The research was also supported by the James Graham Brown Cancer Center (to D. Lee).
All data generated or analyzed during this study are included in this article and its supplementary files. The datasets that were analyzed are available from the corresponding authors on reasonable request.
The preprint of this article is available from bioRxiv at https://doi.org/10.1101/2020.05.24.098665.
Rivas, Dylan R.; Dela Cerna, Mark Vincent C.; Smith, Caroline N.; Sampathi, Shilpa; Patty, Blaine G.; Lee, Donghan; and Blackburn, Jessica S., "A Screen of FDA-Approved Drugs Identifies Inhibitors of Protein Tyrosine Phosphatase 4A3 (PTP4A3 or PRL-3)" (2021). Molecular and Cellular Biochemistry Faculty Publications. 185.