MCC1019,a selective inhibitor of the Polo-box domain of Polo-like kinase 1 as novel,potent anticancer candidate

作     者：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 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

作者机构：Department of Pharmaceutical BiologyInstitute of Pharmacy and BiochemistryJohannes Gutenberg UniversityMainz55128Germany Leipzig UniversityInstitute of Organic ChemistryLeipzig04103Germany State Key Laboratory of Quality Research in Chinese MedicineMacao University of Science and TechnologyMacaoChina MicroCombiChem GmbHWiesbaden65203Germany Abel Salazar Institute of Biomedical SciencesUniversity of PortoPorto4099-003Portugal 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2019年第9卷第5期

页      面：1021-1034页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：partly supported by the Deutsche Forschungsgemeinschaft(DFG INST 268/281-1 FUGG and BE 4572/3-1 Germany) 

主　　题：Polo-like kinase PLK1 Polo box domain Mono-targeted therapy Cell cycle Necroptosis Spindle damage 

摘      要：Polo-like kinase(PLK1) has been identified as a potential target for cancer *** 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 *** 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.