Original articles
Sara Abdelfatah, Angela Berg, Qi Huang, Li Jun Yang, Sami Hamdoun, Anette Klinger, Henry J. Greten, Edmond Fleischer, Thorsten Berg, Vincent K. W. Wong, Thomas Efferth. MCC1019, a selective inhibitor of the Polo-box domain of Polo-like kinase 1 as novel, potent anticancer candidate[J]. Acta Pharmaceutica Sinica B, 2019, 9(5): 1021-1034

MCC1019, a selective inhibitor of the Polo-box domain of Polo-like kinase 1 as novel, potent anticancer candidate
Sara Abdelfataha, Angela Bergb, Qi Huangc, Li Jun Yangc, Sami Hamdouna, Anette Klingerd, Henry J. Gretene, Edmond Fleischerd, Thorsten Bergb, Vincent K. W. Wongc, Thomas Effertha
a Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz 55128, Germany;
b Leipzig University, Institute of Organic Chemistry, Leipzig 04103, Germany;
c State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China;
d MicroCombiChem GmbH, Wiesbaden 65203, Germany;
e Abel Salazar Institute of Biomedical Sciences, University of Porto, Porto 4099-003, Portugal
Polo-like kinase (PLK1) has been identified as a potential target for cancer treatment. Although a number of small molecules have been investigated as PLK1 inhibitors, many of which showed limited selectivity. PLK1 harbors a regulatory domain, the Polo box domain (PBD), which has a key regulatory function for kinase activity and substrate recognition. We report on 3-bromomethylbenzofuran-2-carboxylic acid ethyl ester (designated:MCC1019) as selective PLK1 inhibitor targeting PLK1 PBD. Cytotoxicity and fluorescence polarization-based screening were applied to a library of 1162 drug-like compounds to identify potential inhibitors of PLK1 PBD. The activity of compound MC1019 against the PLK1 PBD was confirmed using fluorescence polarization and microscale thermophoresis.This compound exerted specificity towards PLK1 over PLK2 and PLK3. MCC1019 showed cytotoxic activity in a panel of different cancer cell lines. Mechanistic investigations in A549 lung adenocarcinoma cells revealed that MCC1019 induced cell growth inhibition through inactivation of AKT signaling pathway, it also induced prolonged mitotic arrest-a phenomenon known as mitotic catastrophe, which is followed by immediate cell death via apoptosis and necroptosis. MCC1019 significantly inhibited tumor growth in vivo in a murine lung cancer model without affecting body weight or vital organ size, and reduced the growth of metastatic lesions in the lung. We propose MCC1019 as promising anti-cancer drug candidate.
Key words:    Polo-like kinase    PLK1    Polo box domain    Mono-targeted therapy    Cell cycle    Necroptosis    Spindle damage   
Received: 2018-08-23     Revised: 2018-12-20
DOI: 10.1016/j.apsb.2019.02.001
Funds: This work was partly supported by the Deutsche Forschungsgemeinschaft (DFG INST 268/281-1 FUGG and BE 4572/3-1, Germany). Sara Abdelfatah is grateful to the German Academic Exchange Service (DAAD) for a PhD stipend.
Corresponding author: Thomas Efferth     Email:efferth@uni-mainz.de
Author description:
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Sara Abdelfatah
Angela Berg
Qi Huang
Li Jun Yang
Sami Hamdoun
Anette Klinger
Henry J. Greten
Edmond Fleischer
Thorsten Berg
Vincent K. W. Wong
Thomas Efferth

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