Design, synthesis, and biological evaluation of novel highly selective polo-like kinase 2 inhibitors based on the tetrahydropteridin chemical scaffold
Design, synthesis, and biological evaluation of novel highly selective polo-like kinase 2 inhibitors based on the tetrahydropteridin chemical scaffold
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基于四氢蝶啶化学支架的新型高选择性polo样激酶2抑制剂的设计、合成和生物学评价
DOI：
10.1016/j.ejmech.2017.11.058
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发表时间：
2018-01-01
影响因子：
6.7
通讯作者：
Liao, Chenzhong
中科院分区：
文献类型：
--
作者：
Zhan, Mei-Miao;Yang, Yang;Liao, Chenzhong
Polo 样激酶 2 (Plk2) 是治疗癌症的潜在靶点，在肿瘤细胞增殖和存活中发挥着重要作用。在本报告中，根据Plk1、Plk2和Plk3之间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，设计并合成了两个基于四氢蝶啶化学支架的新型选择性Plk2抑制剂系列，以靶向Plk2的两个特定残基Lys86和Tyr161。评估了所有化合物对 Plk1-Plk3 的抑制活性以及对六种不同人类癌细胞系的细胞抑制活性。所有努力最终从第一系列和第二系列选择性 Plk2 抑制剂中分别鉴定出最有效的化合物 C2（针对 Plk2 为 3.40 nM）和 C21（针对 Plk2 为 4.88 nM）。此外，C21 相对于 Plk1/3 的选择性显着提高，选择性指数分别为 12.57 和 910.06。此外，我们的大多数化合物在 MTT 测定中表现出纳摩尔范围内的抗肿瘤活性，这表明我们的化合物，特别是 C2 和 C21 可能成为有前途的 Plk2 抑制剂，用于进一步的抗癌研究。 (C) 2017 Elsevier Masson SAS。版权所有。
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. (C) 2017 Elsevier Masson SAS. All rights reserved.