MCC1019, a selective inhibitor of the Polo-box domain of Polo-like kinase 1 as novel, potent anticancer candidate.
10.1016/j.apsb.2019.02.001
- Author:
Sara ABDELFATAH
1
;
Angela BERG
2
;
Qi HUANG
3
;
Li Jun YANG
3
;
Sami HAMDOUN
1
;
Anette KLINGER
4
;
Henry J GRETEN
5
;
Edmond FLEISCHER
4
;
Thorsten BERG
2
;
Vincent K W WONG
3
;
Thomas EFFERTH
1
Author Information
1. Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz 55128, Germany.
2. Leipzig University, Institute of Organic Chemistry, Leipzig 04103, Germany.
3. State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
4. MicroCombiChem GmbH, Wiesbaden 65203, Germany.
5. Abel Salazar Institute of Biomedical Sciences, University of Porto, Porto 4099-003, Portugal.
- Publication Type:Journal Article
- Keywords:
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
- From:
Acta Pharmaceutica Sinica B
2019;9(5):1021-1034
- CountryChina
- Language:English
-
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 apoptosis and necroptosis. MCC1019 significantly inhibited tumor growth 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.
