Identification of a novel Polo-like kinase 1 inhibitor that specifically blocks the functions of Polo-Box domain

Yunyu Chen; Jing Zhang; Dongsheng Li; Jiandong Jiang; Yanchang Wang; Shuyi Si

doi:10.18632/oncotarget.13603

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Research Papers:

Identification of a novel Polo-like kinase 1 inhibitor that specifically blocks the functions of Polo-Box domain

Yunyu Chen _, Jing Zhang, Dongsheng Li, Jiandong Jiang, Yanchang Wang and Shuyi Si

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Oncotarget. 2017; 8:1234-1246. https://doi.org/10.18632/oncotarget.13603

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Abstract

Yunyu Chen1,*, Jing Zhang1,*, Dongsheng Li1, Jiandong Jiang1, Yanchang Wang1,2, Shuyi Si1

1Institute of Medicinal Biotechnology, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China

2Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA

*These authors have contributed equally to this work

Correspondence to:

Shuyi Si, email: [email protected]

Yanchang Wang, email: [email protected]

Keywords: Polo-like kinase 1 inhibitor, Polo-Box domain, fluorescence polarization, protein-protein interactions, cancer therapy

Received: September 01, 2015 Accepted: November 11, 2016 Published: November 25, 2016

ABSTRACT

Polo-like kinase 1 (Plk1) is a promising target for cancer therapy due to its essential role in cell division. In addition to a highly conserved kinase domain, Plk1 also contains a Polo-Box domain (PBD), which is essential for Plk1’s subcellular localization and mitotic functions. We adopted a fluorescence polarization assay and identified a new Plk1 PBD inhibitor T521 from a small-molecule compound library. T521 specifically inhibits the PBD of Plk1, but not those of Plk2-3. T521 exhibits covalent binding to some lysine residues of Plk1 PBD, which causes significant changes in the secondary structure of Plk1 PBD. Using a cell-based assay, we showed that T521 impedes the interaction between Plk1 and Bub1, a mitotic checkpoint protein. Moreover, HeLa cells treated with T521 exhibited dramatic mitotic defects. Importantly, T521 suppresses the growth of A549 cells in xenograft nude mice. Taken together, we have identified a novel Plk1 inhibitor that specifically disrupts the functions of Plk1 PBD and shows anticancer activity.

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Research Papers:

Identification of a novel Polo-like kinase 1 inhibitor that specifically blocks the functions of Polo-Box domain

Abstract