Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Hefei University of Technology, Hefei, 230009, China; School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, China.
School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, China.
Eur J Med Chem. 2019 Dec 15;184:111769. doi: 10.1016/j.ejmech.2019.111769. Epub 2019 Oct 11.
Polo-like kinase 1 (Plk1) is a validated target for the treatment of cancer. In this report, by analyzing amino acid residue differences among the ATP-binding pockets of Plk1, Plk2 and Plk3, novel selective Plk1 inhibitors were designed based on BI 2536 and BI 6727, two Plk1 inhibitors in clinical studies for cancer treatments. The Plk1 inhibitors reported herein have more potent inhibition against Plk1 and better isoform selectivity in the Plk family than these two lead compounds. In addition, by introducing a hydroxyl group, our compounds have significantly improved solubility and may target specific polar residues Arg57, Glu69 and Arg134 of Plk1. Moreover, most of our compounds exhibited antitumor activities in the nanomolar range against several cancer cell lines in the MTT assay. Through this structure-based design strategy and SAR study, a few promising selective Plk1 inhibitors having the tetrahydropteridin scaffold, for example, L34, were identified and could be for further anticancer research.
丝氨酸/苏氨酸蛋白激酶 1（Plk1）是癌症治疗的一个有效靶点。在本报告中，通过分析 Plk1、Plk2 和 Plk3 的 ATP 结合口袋中氨基酸残基的差异，基于 BI 2536 和 BI 6727（两种用于癌症治疗的临床研究中的 Plk1 抑制剂）设计了新型选择性 Plk1 抑制剂。与这两种先导化合物相比，本文报道的 Plk1 抑制剂对 Plk1 的抑制作用更强，对 Plk 家族的同工酶选择性更好。此外，通过引入一个羟基，我们的化合物的水溶性得到了显著提高，可能靶向 Plk1 的特定极性残基 Arg57、Glu69 和 Arg134。此外，我们的大多数化合物在 MTT 测定中对几种癌细胞系具有纳摩尔级的抗肿瘤活性。通过这种基于结构的设计策略和 SAR 研究，确定了几个具有四氢蝶呤骨架的有前途的选择性 Plk1 抑制剂，例如 L34，可进一步用于抗癌研究。
