A screen of FDA-approved drugs identifies inhibitors of protein tyrosine phosphatase 4A3 (PTP4A3 or PRL-3)

Dylan R. Rivas, Mark Vincent C. Dela Cerna, Caroline N. Smith, Shilpa Sampathi, Blaine G. Patty, Donghan Lee, Jessica S. Blackburn

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number10302
JournalScientific Reports
Volume11
Issue number1
DOIs
StatePublished - Dec 2021

Bibliographical note

Funding Information:
We thank Dr. Vivek Ragnakar (University of Kentucky) for providing the FDA approved library, and Zhong-Ying Zhang (Purdue University) for providing Thienopryridone. We thank Konstantin Korotkov (University of Kentucky) for assistance with generating Pymol structures. 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).

Publisher Copyright:
© 2021, The Author(s).

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'A screen of FDA-approved drugs identifies inhibitors of protein tyrosine phosphatase 4A3 (PTP4A3 or PRL-3)'. Together they form a unique fingerprint.

Cite this