The serine/threonine kinase Polo-like kinase 1 (Plk1) plays a pivotal role in cell proliferation and has been validated as a promising anticancer drug target. However, very limited success has been achieved in clinical applications using existing Plk1 inhibitors, due to lack of sufficient specificity toward Plk1. To develop a novel Plk1 inhibitor with high selectivity and efficacy, we designed and synthesized a pyrrole-imidazole polyamide–Hoechst conjugate, PIP3, targeted to specific DNA sequence in the PLK1 promoter. PIP3 could specifically inhibit the cell cycle–regulated Plk1 expression and consequently retard tumor cell growth. Cancer cells treated with PIP3 exhibited severe mitotic defects and increased apoptosis, whereas normal cells were not affected by PIP3 treatment. Furthermore, subcutaneous injection of PIP3 into mice bearing human cancer xenografts induced significant tumor growth suppression with low host toxicity. Therefore, PIP3 exhibits the potential as an effective agent for targeted cancer therapy. Mol Cancer Ther; 17(5); 988–1002. ©2018 AACR.

中文翻译：

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新型吡咯-咪唑聚酰胺-Hoechst 缀合物靶向 Polo 样激酶 1 可抑制体内肿瘤生长


丝氨酸/苏氨酸激酶 Polo 样激酶 1 (Plk1) 在细胞增殖中发挥着关键作用，已被验证为有前途的抗癌药物靶点。然而，由于对 Plk1 缺乏足够的特异性，使用现有 Plk1 抑制剂在临床应用中取得的成功非常有限。为了开发一种具有高选择性和有效性的新型 Plk1 抑制剂，我们设计并合成了吡咯-咪唑聚酰胺-Hoechst 缀合物 PIP3，其靶向 PLK1 启动子中的特定 DNA 序列。 PIP3 可以特异性抑制细胞周期调节的 Plk1 表达，从而延缓肿瘤细胞的生长。用 PIP3 处理的癌细胞表现出严重的有丝分裂缺陷和细胞凋亡增加，而正常细胞则不受 PIP3 处理的影响。此外，将 PIP3 皮下注射到携带人类癌症异种移植物的小鼠体内，可诱导显着的肿瘤生长抑制，且宿主毒性较低。因此，PIP3 显示出作为靶向癌症治疗的有效药物的潜力。摩尔癌症治疗； 17(5)； 988–1002。 ©2018 AACR。