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

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

doi:10.1038/s41598-021-89668-5

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.

Highlights

Protein tyrosine phosphatase 4A3 (PTP4A3 or phosphatase of regenerating liver (PRL)-3) is highly expressed in a variety of cancers, where it promotes tumor cell migration and metastasis leading to poor prognosis
Less studied than PRL-3, data indicate that PRL-1 and PRL-2 overexpression increases metastasis in mouse models, while their loss decreases tumor cell migration and invasion
Phosphatase activities of recombinantly expressed PRL-1, PRL-2, and PRL-3 were evaluated based on their ability to hydrolyze the synthetic substrate, phospho-tyrosine analog 6,8-Difluoro-4-methylumbelliferyl phosphate (DiFMUP)

Summary

Introduction

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. 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. Protein tyrosine phosphatases (PTPs), in particular, have emerged as central regulators of cancer development and progression, with their increased activity correlated to enhanced tumor formation in mouse models and worse prognosis in p atients[2,3,4,5]. Less studied than PRL-3, data indicate that PRL-1 and PRL-2 overexpression increases metastasis in mouse models, while their loss decreases tumor cell migration and invasion Together these results demonstrate the importance of the PRL family both in tumor formation and cancer progression, which has made them attractive therapeutic targets

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