期刊
MOLECULAR CANCER THERAPEUTICS
卷 17, 期 5, 页码 988-1002出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-17-0747
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资金
- Ministry of Science and Technology of China [2014CB964602]
- National Natural Science Foundation of China [31671397, 21402232, 21778068, 21672254, 21432003, 81702952, 31601174, 81502537]
- Guangdong Natural Science Foundation of Research Team [2016A030312006]
- Guangdong Natural Science Foundation [2016A030310128]
- Shenzhen Science and Technology Program [JCYJ20160229204338907, JCYJ20150630114942300, JCYJ20150401150223649, JCYJ20170307165752275, JCYJ20170818153538196, KQCX 2015033117354154]
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. (C) 2018 AACR.
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