Targeting Polo-like Kinase 1 by a Novel Pyrrole-Imidazole Polyamide-Hoechst Conjugate Suppresses Tumor Growth In Vivo

• Published in: Molecular cancer therapeutics 2018-05, Vol.17 (5), p.988-1002
• Main Authors: Liu, Ke, Fang, Lijing, Sun, Haiyan, Pan, Zhengyin, Zhang, Jianchao, Chen, Juntao, Shao, Ximing, Wang, Wei, Tan, Yuanyan, Ding, Zhihao, Ao, Lijiao, Wu, Chunlei, Liu, Xiaoqi, Li, Huashun, Wang, Rui, Su, Wu, Li, Hongchang
• Format: Article
• Language: English
• Subjects: A549 Cells; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Biocompatibility; Cancer; Cell cycle; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cells, Cultured; Deoxyribonucleic acid; DNA; Female; Fluorescent Dyes - chemistry; HeLa Cells; Humans; Imidazole; Imidazoles - chemistry; Kinases; Mice, Inbred BALB C; Mice, Nude; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - pathology; Nucleotide sequence; Nylons - chemistry; Phosphatidylinositol 3,4,5-triphosphate; Polo-like kinase; Polo-Like Kinase 1; Polyamide resins; Polyamides; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein-serine/threonine kinase; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Pyrroles - chemistry; Therapeutic applications; Toxicity; Tumors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.mct-17-0747

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 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. .