Institute of Molecular Science, Key Laboratory of Chemical Biology and Molecular Engineering of the Education Ministry, Shanxi University, Taiyuan, Shanxi 030006, People's Republic of China; Department of Security, Shanxi Police College, Taiyuan, Shanxi 030401, People's Republic of China.
Institute of Molecular Science, Key Laboratory of Chemical Biology and Molecular Engineering of the Education Ministry, Shanxi University, Taiyuan, Shanxi 030006, People's Republic of China.
Bioorg Med Chem Lett. 2021 Jun 1;41:127981. doi: 10.1016/j.bmcl.2021.127981. Epub 2021 Mar 22.
Increasing evidences demonstrated that PRL-3 was associated with metastatic potential in a variety of cancers including CRC, gastric cancer, ovarian cancer and so on. PRL-3 knock down inhibited the development of metastasis by reducing the size of primary tumors and inhibiting the invasion and growth of cancer cells. Therefore, PRL-3 is a promising diagnostic marker and therapeutic target in tumors. So far, only several PRL-3 inhibitors have been reported. In this study, six rhodanine derivatives were synthesized and characterized. The compounds were evaluated against tyrosine phosphatase PRL-3. Among these compounds, 5-(5-chloro-2-(trifluoromethyl)benzylidene)-2-thioxothiazolidin-4-one (4) could effectively inhibit PRL-3 with IC value of 15.22 μM. Fluorescent assays suggested compound 4 tightly bound to tyrosine phosphatase PRL-3 with the molar ratio of 1:1, and the binding constant of 1.74 × 10 M. Compound 4 entered into SW-480 cells, selectively inhibited the expression of PRL-3 and increased the phosphorylation of PRL-3 substrates, and decreased the survival rate of SW-480 cells with IC of 6.64 μM and induced apoptosis. The results revealed that compound 4 is a dual functional inhibitor against the activity and expression of PRL-3 and a promising anti-cancer candidate targeting PRL-3.
越来越多的证据表明，PRL-3 与包括 CRC、胃癌、卵巢癌等在内的多种癌症的转移潜能有关。PRL-3 的敲低通过减小原发性肿瘤的大小并抑制癌细胞的侵袭和生长，从而抑制转移的发展。因此，PRL-3 是肿瘤中一种有前途的诊断标志物和治疗靶点。到目前为止，仅报道了几种 PRL-3 抑制剂。在这项研究中，合成并表征了六种罗丹宁衍生物。这些化合物针对酪氨酸磷酸酶 PRL-3 进行了评估。在这些化合物中，5-(5-氯-2-(三氟甲基)苯亚甲基)-2-硫代噻唑烷-4-酮（4）可以有效抑制 PRL-3，IC 值为 15.22 μM。荧光测定表明化合物 4 与酪氨酸磷酸酶 PRL-3 紧密结合，摩尔比为 1:1，结合常数为 1.74×10 M。化合物 4 进入 SW-480 细胞，选择性抑制 PRL-3 的表达并增加 PRL-3 底物的磷酸化，降低 SW-480 细胞的存活率，IC 为 6.64 μM，并诱导细胞凋亡。结果表明，化合物 4 是一种针对 PRL-3 的活性和表达的双功能抑制剂，是一种有前途的靶向 PRL-3 的抗癌候选药物。
