Abstract

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.

Document Type

Article

Publication Date

5-13-2021

Notes/Citation Information

Published in Scientific Reports, v. 11, issue 1, article no. 10302.

© The Author(s) 2021

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.

Digital Object Identifier (DOI)

https://doi.org/10.1038/s41598-021-89668-5

Funding Information

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).

Related Content

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.

41598_2021_89668_MOESM1_ESM.pdf (5377 kB)
Supplementary information 1

41598_2021_89668_MOESM2_ESM.xlsx (102 kB)
Supplementary information 2

Share

COinS