Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory on Protein Chemistry and Structural Biology, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory on Protein Chemistry and Structural Biology, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing 210009, China.
Bioorg Chem. 2019 Apr;85:534-540. doi: 10.1016/j.bioorg.2019.02.022. Epub 2019 Feb 11.
A series of d-amino acid-containing peptidomimetics were designed, synthesized as novel polo-like kinase 1 (Plk1) polo-box domain (PBD) inhibitors based on the reported peptide Plk1 PBD inhibitor. Their inhibitory activity to Plk1, Plk2, and Plk3 PBD were evaluated using our fluorescence polarization (FP) assay. Compound 18 bound to Plk1 PBD with IC of 0.80 μM and showed nearly no inhibition to Plk2 PBD or Plk3 PBD at 100 μM. Compound 18 induced Hela cells to undergo apoptosis by increasing the ratio of the cells at the G2/M phase by decreasing the neosynthesized proteins in a dose-dependent manner from 50 to 150 μM. Compound 18 showed improved stability in rat plasma compared to l-peptide inhibitor LHSpTA. These novel d-amino acid modified selective Plk1 PBD inhibitors may provide new lead compounds for further optimization.
设计并合成了一系列含有 D-氨基酸的肽模拟物，作为新型的丝氨酸/苏氨酸激酶 1（Plk1） polo -box 结构域（PBD）抑制剂，基于报道的肽 Plk1 PBD 抑制剂。使用我们的荧光偏振（FP）测定法评估了它们对 Plk1、Plk2 和 Plk3 PBD 的抑制活性。化合物 18 与 Plk1 PBD 的 IC 为 0.80μM，在 100μM 时对 Plk2 PBD 或 Plk3 PBD 几乎没有抑制作用。化合物 18 通过降低新合成的蛋白质的量，以剂量依赖的方式将细胞从 50 至 150μM 时在 G2/M 期的细胞比例增加，从而诱导 Hela 细胞发生凋亡。与 L-肽抑制剂 LHSpTA 相比，化合物 18 在大鼠血浆中的稳定性得到改善。这些新型的 D-氨基酸修饰的选择性 Plk1 PBD 抑制剂可能为进一步优化提供新的先导化合物。
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