Polo-like kinase 2 (Plk2) is a potential target for the treatment of cancer, which displays an important role in tumor cell proliferation and survival. In this report, according to the analysis of critical amino acid residue differences among Plk1, Plk2 and Plk3, and structure-based drug design strategies, two novel series of selective Plk2 inhibitors based on tetrahydropteridin chemical scaffold were designed and synthesized to target two specific residues, Lys86 and Tyr161 of Plk2. All compounds were evaluated for their inhibitory activity against Plk1-Plk3 and the cellular inhibition activity on six different human cancer cell lines. All efforts led to the identification of the most potent compounds C2 (3.40 nM against Plk2) and C21 (4.88 nM against Plk2) from the first and second series of selective Plk2 inhibitors respectively. Additionally, the selectivity of C21 over Plk1/3 was significantly increased with the selectivity indexes of 12.57 and 910.06. Moreover, most of our compounds exhibited antitumor activity in the nanomolar range in the MTT assay, indicating that our compounds, especially C2 and C21 could be promising Plk2 inhibitors for further anticancer research.

Polo样激酶2（Plk2）是治疗癌症的潜在靶标，它在肿瘤细胞的增殖和存活中发挥重要作用。在本报告中，根据对Plk1，Plk2和Plk3的关键氨基酸残基差异的分析，以及基于结构的药物设计策略，设计并合成了两种新的基于四氢蝶呤化学支架的选择性Plk2抑制剂系列，以靶向两个特定残基，Plk2的Lys86和Tyr161。评价所有化合物对Plk1-Plk3的抑制活性以及对六种不同人癌细胞系的细胞抑制活性。所有的努力导致鉴定出最有效的化合物C2（针对Plk2的化合物为3.40 nM）和C21（来自Plk2抑制剂的第一和第二系列）（抗Plk2为4.88 nM）。此外，选择性C21以上的Plk1 / 3的12.57和910.06选择性索引被显著增加。此外，我们的大多数化合物在MTT分析中均显示出纳摩尔级的抗肿瘤活性，这表明我们的化合物（尤其是C2和C21）可能是有望用于进一步抗癌研究的Plk2抑制剂。