Abstract
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.
Original language | English |
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Pages (from-to) | 988-1002 |
Number of pages | 15 |
Journal | Molecular Cancer Therapeutics |
Volume | 17 |
Issue number | 5 |
DOIs | |
State | Published - May 2018 |
Bibliographical note
Publisher Copyright:© 2018 American Association for Cancer Research.
Funding
This work was supported by a grant from the Ministry of Science and Technology of China no. 2014CB964602 (to H.C. Li); National Natural Science Foundation of China no. 31671397 (to H.C. Li), no. 21402232, and no. 21778068 (to L.J. Fang), no. 21672254 and no. 21432003 (to W. Su), no. 81702952 (to K. Liu), no. 31601174 (to X.M. Shao), no. 81502537 (to J.C. Zhang); Guangdong Natural Science Foundation of Research Team no. 2016A030312006 (to H.C. Li and W. Su); Guangdong Natural Science Foundation no. 2016A030310128 (to J.C. Zhang); Shenzhen Science and Technology Program JCYJ20160229204338907 and JCYJ20150630114942300 (to H. C. Li), JCYJ20150401150223649 (to W. Wang), JCYJ20170307165752275 (to K. Liu), JCYJ20170818153538196 (to W. Su), and KQCX 2015033117354154 (to L.J. Fang). This work was supported by a grant from the Ministry of Science and Technology of China no. 2014CB964602 (to H.C. Li); National Natural Science Foundation of China no. 31671397 (to H.C. Li), no. 21402232, and no. 21778068 (to L.J. Fang), no. 21672254 and no. 21432003 (to W. Su), no. 81702952 (to K. Liu), no. 31601174 (to X.M. Shao), no. 81502537 (to J.C. Zhang); Guangdong Natural Science Foundation of Research Team no. 2016A030312006 (to H.C. Li and W. Su); Guangdong Natural Science Foundation no. 2016A030310128 (to J.C. Zhang); Shenzhen Science and Technology Program JCYJ20160229204338907 and JCYJ20150630114942300 (to H. C. Li), JCYJ20150401150223649 (to W. Wang), JCYJ20170307165752275 (to
Funders | Funder number |
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Guangdong Natural Science Foundation of Research Team | |
Ministry of Science and Technology, China | |
Shenzhen Science and Technology Program | JCYJ20160229204338907, JCYJ20170307165752275, JCYJ20150630114942300, JCYJ20150401150223649 |
National Natural Science Foundation of China (NSFC) | 21432003, Su, 81502537, 31601174, 21402232, 21778068, 31671397, 21672254, 81702952 |
Ministry of Science and Technology of the People's Republic of China | 2014CB964602 |
Natural Science Foundation of Guangdong Province | 2016A030312006, 2016A030310128 |
Shenzhen Graduate School, Peking University | |
Ministry of Science and Technology, Government of the People’s Republic of Bangladesh | |
Shenzhen Technology Development Program | KQCX 2015033117354154, JCYJ20170818153538196 |
ASJC Scopus subject areas
- Oncology
- Cancer Research