Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA.
Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, 40202, USA.
Sci Rep. 2021 May 13;11(1):10302. doi: 10.1038/s41598-021-89668-5.
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 CXR motif. Inhibitor binding at either of these sites is predicted to trap PRL-3 in a closed conformation, preventing substrate binding and inhibiting function.
蛋白酪氨酸磷酸酶 4A3（PTP4A3 或 PRL-3）在多种癌症中高度表达，它促进肿瘤细胞迁移和转移，导致预后不良。尽管其具有临床意义，但缺乏 PRL-3 的小分子抑制剂。在这里，我们筛选了 1443 种已批准用于临床的药物，以评估它们抑制 PRL 磷酸酶家族活性的能力。我们确定了五种针对 PRL-3 的特异性抑制剂和一种针对 PRL-2 的选择性抑制剂。此外，我们还发现了九种能够广泛且显著抑制 PRL 活性的药物。其中两种广谱 PRL 抑制剂——Salirasib 和坎地沙坦，可阻止 PRL-3 诱导的人胚肾细胞迁移，而对细胞活力没有影响。这两种药物都以 PRL-3 依赖的方式阻止了人结直肠癌细胞的迁移，并且对 PRL 相对于其他磷酸酶具有选择性。基于计算机的建模表明，Salirasib 结合 PRL-3 的 WPD 环附近的一个假定别构位点，而坎地沙坦结合 CXR 基序附近的一个潜在新靶位。这两个位点的抑制剂结合预计会将 PRL-3 捕获在封闭构象中，从而阻止底物结合并抑制其功能。
