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

Publication type:
Journal article
Metadata:
Autoren
  • Sara Abdelfatah
  • Angela Berg
  • Qi Huang
  • Li Jun Yang
  • Sami Hamdoun
  • Anette Klinger
  • Henry J Greten
  • Edmond Fleischer
  • Thorsten Berg
  • Vincent KW Wong
  • Thomas Efferth
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000487282700012&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1016/j.apsb.2019.02.001
eISSN
2211-3843
Externe Identifier
  • Clarivate Analytics Document Solution ID: IZ7NU
  • PubMed Identifier: 31649851
ISSN
2211-3835
Ausgabe der Veröffentlichung
5
Zeitschrift
ACTA PHARMACEUTICA SINICA B
Schlüsselwörter
  • Polo-like kinase
  • PLK1
  • Polo box domain
  • Mono-targeted therapy
  • Cell cycle
  • Necroptosis
  • Spindle damage
Paginierung
1021 - 1034
Datum der Veröffentlichung
2019
Status
Published
Titel
MCC1019, a selective inhibitor of the Polo-box domain of Polo-like kinase 1 as novel, potent anticancer candidate
Sub types
  • Article
Ausgabe der Zeitschrift
9

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • Sara Abdelfatah
  • Angela Berg
  • Qi Huang
  • Li Jun Yang
  • Sami Hamdoun
  • Anette Klinger
  • Henry J Greten
  • Edmond Fleischer
  • Thorsten Berg
  • Vincent KW Wong
  • Thomas Efferth
DOI
10.1016/j.apsb.2019.02.001
ISSN
2211-3835
Ausgabe der Veröffentlichung
5
Zeitschrift
Acta Pharmaceutica Sinica B
Sprache
en
Paginierung
1021 - 1034
Datum der Veröffentlichung
2019
Status
Published
Herausgeber
Elsevier BV
Herausgeber URL
http://dx.doi.org/10.1016/j.apsb.2019.02.001
Datum der Datenerfassung
2022
Titel
MCC1019, a selective inhibitor of the Polo-box domain of Polo-like kinase 1 as novel, potent anticancer candidate
Ausgabe der Zeitschrift
9

Data source: Crossref

Abstract
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-bromomethyl-benzofuran-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 <i>via</i> apoptosis and necroptosis. MCC1019 significantly inhibited tumor growth <i>in vivo</i> 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.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz 55128, Germany.
Autoren
  • Sara Abdelfatah
  • Angela Berg
  • Qi Huang
  • Li Jun Yang
  • Sami Hamdoun
  • Anette Klinger
  • Henry J Greten
  • Edmond Fleischer
  • Thorsten Berg
  • Vincent KW Wong
  • Thomas Efferth
DOI
10.1016/j.apsb.2019.02.001
eISSN
2211-3843
Externe Identifier
  • PubMed Identifier: 31649851
  • PubMed Central ID: PMC6804483
Funding acknowledgements
  • Deutsche Forschungsgemeinschaft: DFG INST 268/281-1 FUGG
  • Deutsche Forschungsgemeinschaft: BE 4572/3-1
  • German Academic Exchange Service:
Open access
true
ISSN
2211-3835
Ausgabe der Veröffentlichung
5
Zeitschrift
Acta pharmaceutica Sinica. B
Sprache
eng
Medium
Print-Electronic
Online publication date
2019
Open access status
Open Access
Paginierung
1021 - 1034
Datum der Veröffentlichung
2019
Status
Published
Publisher licence
CC BY-NC-ND
Datum der Datenerfassung
2019
Titel
MCC1019, a selective inhibitor of the Polo-box domain of Polo-like kinase 1 as novel, potent anticancer candidate.
Sub types
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
9

Files

https://europepmc.org/articles/PMC6804483?pdf=render

Data source: Europe PubMed Central

Abstract
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-bromomethyl-benzofuran-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.
Date of acceptance
2018
Autoren
  • Sara Abdelfatah
  • Angela Berg
  • Qi Huang
  • Li Jun Yang
  • Sami Hamdoun
  • Anette Klinger
  • Henry J Greten
  • Edmond Fleischer
  • Thorsten Berg
  • Vincent KW Wong
  • Thomas Efferth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/31649851
DOI
10.1016/j.apsb.2019.02.001
Externe Identifier
  • PubMed Central ID: PMC6804483
ISSN
2211-3835
Ausgabe der Veröffentlichung
5
Zeitschrift
Acta Pharm Sin B
Schlüsselwörter
  • 3-MA, 3-methyladenine
  • ABC, avidin-biotin complex
  • APC/C, anaphase-promoting complex/cyclosome
  • BUBR1, budding uninhibited by benzimidazole-related 1
  • CDC2, cell division cycle protein 2 homolog
  • CDC25, cell division cycle 25
  • CDK, cyclin-dependent kinase
  • Cell cycle
  • DAPI, 4′,6-diamidino-2-phenylindole
  • DAPKs, death-associated protein kinase
  • FBS, fetal bovine serum
  • FOXO, forkhead box O
  • HIF-1α, hypoxia-inducible factor 1 α
  • IC50, 50% inhibition concentration
  • IHC, immunohistochemistry
  • Kd, the dissociation constant
  • LC3, light chain 3
  • MFP, M phase promoting factor
  • MST, microscale thermophoresis
  • MTD, maximal tolerance dose
  • Mono-targeted therapy
  • Nec-1, necrostatin 1
  • Necroptosis
  • PARP-1, poly(ADP-ribose) polymerase-1
  • PBD, Polo box domain
  • PDB, Protein Data Bank
  • PI, propidium iodide
  • PLK1
  • PLK1, Polo-like kinase
  • Polo box domain
  • Polo-like kinase
  • SAC, spindle assembly checkpoint
  • Spindle damage
Sprache
eng
Country
Netherlands
Paginierung
1021 - 1034
PII
S2211-3835(18)30827-X
Datum der Veröffentlichung
2019
Status
Published
Titel
MCC1019, a selective inhibitor of the Polo-box domain of Polo-like kinase 1 as novel, potent anticancer candidate.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
9

Data source: PubMed

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