MCC1019, a selective inhibitor of the Polo-box domain of Polo-like kinase 1 as novel, potent anticancer candidate.
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
Journal
Acta pharmaceutica Sinica. B
ISSN: 2211-3835
Titre abrégé: Acta Pharm Sin B
Pays: Netherlands
ID NLM: 101600560
Informations de publication
Date de publication:
Sep 2019
Sep 2019
Historique:
received:
23
08
2018
revised:
20
12
2018
accepted:
22
12
2018
entrez:
26
10
2019
pubmed:
28
10
2019
medline:
28
10
2019
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 31649851
doi: 10.1016/j.apsb.2019.02.001
pii: S2211-3835(18)30827-X
pmc: PMC6804483
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1021-1034Informations de copyright
© 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
Références
EMBO J. 1998 Mar 2;17(5):1328-35
pubmed: 9482730
Breast Cancer Res. 2012 Feb 06;14(1):R22
pubmed: 22309939
Blood. 2006 Jan 1;107(1):250-6
pubmed: 16160013
J Clin Oncol. 2016 Mar 1;34(7):706-13
pubmed: 26755507
Anal Biochem. 2008 Dec 15;383(2):205-9
pubmed: 18793607
ACS Chem Biol. 2013 Feb 15;8(2):303-8
pubmed: 23135290
EMBO Rep. 2002 Apr;3(4):341-8
pubmed: 11897663
Biochim Biophys Acta. 2011 Nov;1813(11):1978-86
pubmed: 21440011
Apoptosis. 2002 Aug;7(4):321-8
pubmed: 12101391
Chembiochem. 2016 Apr 15;17(8):650-6
pubmed: 26662918
Nat Cell Biol. 2003 Feb;5(2):143-8
pubmed: 12524548
Nat Chem Biol. 2006 Nov;2(11):618-26
pubmed: 17028580
Nat Rev Cancer. 2005 Oct;5(10):773-85
pubmed: 16195750
Curr Opin Cell Biol. 2001 Apr;13(2):167-71
pubmed: 11248550
Nat Rev Cancer. 2002 Jul;2(7):489-501
pubmed: 12094235
Mol Oncol. 2014 May;8(3):596-608
pubmed: 24484936
Braz Oral Res. 2009 Jul-Sep;23(3):255-62
pubmed: 19893959
Curr Opin Cell Biol. 1998 Dec;10(6):776-83
pubmed: 9914175
Assay Drug Dev Technol. 2011 Aug;9(4):342-53
pubmed: 21812660
Cell. 2003 Oct 3;115(1):83-95
pubmed: 14532005
Mol Ther. 2011 May;19(5):928-35
pubmed: 21364537
ChemMedChem. 2008 Jun;3(6):885-97
pubmed: 18384086
Trends Biochem Sci. 2014 Apr;39(4):159-69
pubmed: 24630600
Oncologist. 2009 Jun;14(6):559-70
pubmed: 19474163
Blood. 2014 Aug 28;124(9):1426-33
pubmed: 25006120
Chem Biol. 2008 May;15(5):459-66
pubmed: 18482698
Oncol Rep. 2016 Jul;36(1):49-56
pubmed: 27220401
Adv Enzyme Regul. 2000;40:183-215
pubmed: 10828352
Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):4882-6
pubmed: 8099445
Am J Transl Res. 2016 Oct 15;8(10):4172-4183
pubmed: 27830001
Biochem Pharmacol. 2017 Dec 15;146:63-73
pubmed: 29061340
Acta Pharm Sin B. 2015 Sep;5(5):378-89
pubmed: 26579469
Biochem Pharmacol. 2010 Mar 15;79(6):926-37
pubmed: 19883628
J Biol Chem. 2007 May 18;282(20):15217-27
pubmed: 17376779
Nat Rev Cancer. 2017 Sep;17(9):528-542
pubmed: 28751651
Oncotarget. 2017 Jul 5;8(33):55003-55021
pubmed: 28903398
Oncotarget. 2016 Mar 29;7(13):16818-39
pubmed: 26921194
Philos Trans R Soc Lond B Biol Sci. 2011 Dec 27;366(1584):3494-7
pubmed: 22084376
Oncotarget. 2014 May 30;5(10):3130-44
pubmed: 24931513
Angew Chem Int Ed Engl. 2012 Oct 15;51(42):10656-9
pubmed: 23001866
Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):1984-9
pubmed: 11854496
Redox Biol. 2015 Dec;6:51-72
pubmed: 26184557
Oncogene. 2005 Jan 10;24(2):248-59
pubmed: 15640840
Cell Res. 2014 Sep;24(9):1141-5
pubmed: 24980956
Biosci Rep. 2017 Jul 19;:null
pubmed: 28724602
Nature. 2001 Mar 8;410(6825):215-20
pubmed: 11242082
Molecules. 2017 Mar 13;22(3):
pubmed: 28335397
J Biol Chem. 2009 Feb 20;284(8):5332-42
pubmed: 19098000
Biochim Biophys Acta. 2011 Nov;1813(11):1938-45
pubmed: 21708191
Nat Chem Biol. 2011 Jul 17;7(9):595-601
pubmed: 21765407
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3107-12
pubmed: 17307877
J Cell Sci. 1994 Jun;107 ( Pt 6):1509-17
pubmed: 7962193
Invest New Drugs. 2014 Aug;32(4):618-25
pubmed: 24748336
Clin Cancer Res. 2009 May 1;15(9):3094-102
pubmed: 19383823
Cancer Sci. 2006 Apr;97(4):271-6
pubmed: 16630118
Cell Cycle. 2014;13(11):1727-36
pubmed: 24675888
Anal Biochem. 2009 Dec 15;395(2):189-94
pubmed: 19716361
Cancer Res. 2008 Jun 1;68(11):4077-85
pubmed: 18519666