Targeting polo-like kinase 1 by a novel pyrrole-imidazole polyamide–hoechst conjugate suppresses tumor growth in vivo

Ke Liu, Lijing Fang, Haiyan Sun, Zhengyin Pan, Jianchao Zhang, Juntao Chen, Ximing Shao, Wei Wang, Yuanyan Tan, Zhihao Ding, Lijiao Ao, Chunlei Wu, Xiaoqi Liu, Huashun Li, Rui Wang, Wu Su, Hongchang Li

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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 languageEnglish
Pages (from-to)988-1002
Number of pages15
JournalMolecular Cancer Therapeutics
Volume17
Issue number5
DOIs
StatePublished - 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

FundersFunder number
Guangdong Natural Science Foundation of Research Team
Ministry of Science and Technology, China
Shenzhen Science and Technology ProgramJCYJ20160229204338907, 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 China2014CB964602
Natural Science Foundation of Guangdong Province2016A030312006, 2016A030310128
Shenzhen Graduate School, Peking University
Ministry of Science and Technology, Government of the People’s Republic of Bangladesh
Shenzhen Technology Development ProgramKQCX 2015033117354154, JCYJ20170818153538196

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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